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Journal articles on the topic 'Autophagic receptors'
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1
Kimura, Tomonori, Ashish Jain, Seong Won Choi, Michael A. Mandell, Kate Schroder, Terje Johansen, and Vojo Deretic. "TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity." Journal of Cell Biology 210, no. 6 (September 7, 2015): 973–89. http://dx.doi.org/10.1083/jcb.201503023.
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The present paradigms of selective autophagy in mammalian cells cannot fully explain the specificity and selectivity of autophagic degradation. In this paper, we report that a subset of tripartite motif (TRIM) proteins act as specialized receptors for highly specific autophagy (precision autophagy) of key components of the inflammasome and type I interferon response systems. TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro–caspase 1, for autophagic degradation, whereas TRIM21 targets IRF3. TRIM20 and TRIM21 directly bind their respective cargo and recruit autophagic machinery to execute degradation. The autophagic function of TRIM20 is affected by mutations associated with familial Mediterranean fever. These findings broaden the concept of TRIMs acting as autophagic receptor regulators executing precision autophagy of specific cytoplasmic targets. In the case of TRIM20 and TRIM21, precision autophagy controls the hub signaling machineries and key factors, inflammasome and type I interferon, directing cardinal innate immunity response systems in humans.
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Lin, Long, Peiguo Yang, Xinxin Huang, Hui Zhang, Qun Lu, and Hong Zhang. "The scaffold protein EPG-7 links cargo–receptor complexes with the autophagic assembly machinery." Journal of Cell Biology 201, no. 1 (March 25, 2013): 113–29. http://dx.doi.org/10.1083/jcb.201209098.
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The mechanism by which protein aggregates are selectively degraded by autophagy is poorly understood. Previous studies show that a family of Atg8-interacting proteins function as receptors linking specific cargoes to the autophagic machinery. Here we demonstrate that during Caenorhabditis elegans embryogenesis, epg-7 functions as a scaffold protein mediating autophagic degradation of several protein aggregates, including aggregates of the p62 homologue SQST-1, but has little effect on other autophagy-regulated processes. EPG-7 self-oligomerizes and is degraded by autophagy independently of SQST-1. SQST-1 directly interacts with EPG-7 and colocalizes with EPG-7 aggregates in autophagy mutants. Mutations in epg-7 impair association of SQST-1 aggregates with LGG-1/Atg8 puncta. EPG-7 interacts with multiple ATG proteins and colocalizes with ATG-9 puncta in various autophagy mutants. Unlike core autophagy genes, epg-7 is dispensable for starvation-induced autophagic degradation of substrate aggregates. Our results indicate that under physiological conditions a scaffold protein endows cargo specificity and also elevates degradation efficiency by linking the cargo–receptor complex with the autophagic machinery.
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Luo, Shuwei, Xifeng Li, Yan Zhang, Yunting Fu, Baofang Fan, Cheng Zhu, and Zhixiang Chen. "Cargo Recognition and Function of Selective Autophagy Receptors in Plants." International Journal of Molecular Sciences 22, no. 3 (January 20, 2021): 1013. http://dx.doi.org/10.3390/ijms22031013.
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Autophagy is a major quality control system for degradation of unwanted or damaged cytoplasmic components to promote cellular homeostasis. Although non-selective bulk degradation of cytoplasm by autophagy plays a role during cellular response to nutrient deprivation, the broad roles of autophagy are primarily mediated by selective clearance of specifically targeted components. Selective autophagy relies on cargo receptors that recognize targeted components and recruit them to autophagosomes through interaction with lapidated autophagy-related protein 8 (ATG8) family proteins anchored in the membrane of the forming autophagosomes. In mammals and yeast, a large collection of selective autophagy receptors have been identified that mediate the selective autophagic degradation of organelles, aggregation-prone misfolded proteins and other unwanted or nonnative proteins. A substantial number of selective autophagy receptors have also been identified and functionally characterized in plants. Some of the autophagy receptors in plants are evolutionarily conserved with homologs in other types of organisms, while a majority of them are plant-specific or plant species-specific. Plant selective autophagy receptors mediate autophagic degradation of not only misfolded, nonactive and otherwise unwanted cellular components but also regulatory and signaling factors and play critical roles in plant responses to a broad spectrum of biotic and abiotic stresses. In this review, we summarize the research on selective autophagy in plants, with an emphasis on the cargo recognition and the biological functions of plant selective autophagy receptors.
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Chang, Chunmei, Xiaoshan Shi, Liv E. Jensen, Adam L. Yokom, Dorotea Fracchiolla, Sascha Martens, and James H. Hurley. "Reconstitution of cargo-induced LC3 lipidation in mammalian selective autophagy." Science Advances 7, no. 17 (April 2021): eabg4922. http://dx.doi.org/10.1126/sciadv.abg4922.
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Selective autophagy of damaged mitochondria, protein aggregates, and other cargoes is essential for health. Cargo initiates phagophore biogenesis, which entails the conjugation of LC3 to phosphatidylethanolamine. Current models suggest that clustered ubiquitin chains on a cargo trigger a cascade from autophagic cargo receptors through the core complexes ULK1 and class III phosphatidylinositol 3-kinase complex I, WIPI2, and the ATG7, ATG3, and ATG12ATG5-ATG16L1 machinery of LC3 lipidation. This was tested using giant unilamellar vesicles (GUVs), GST-Ub4 as a model cargo, the cargo receptors NDP52, TAX1BP1, and OPTN, and the autophagy core complexes. All three cargo receptors potently stimulated LC3 lipidation on GUVs. NDP52- and TAX1BP1-induced LC3 lipidation required all components, but not ULK1 kinase activity. However, OPTN bypassed the ULK1 requirement. Thus, cargo-dependent stimulation of LC3 lipidation is common to multiple autophagic cargo receptors, yet the details of core complex engagement vary between the different receptors.
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Valenzuela, Cristián A., Marco Azúa, Claudio A. Álvarez, Paulina Schmitt, Nicolás Ojeda, and Luis Mercado. "Evidence of the Autophagic Process during the Fish Immune Response of Skeletal Muscle Cells against Piscirickettsia salmonis." Animals 13, no. 5 (February 28, 2023): 880. http://dx.doi.org/10.3390/ani13050880.
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Autophagy is a fundamental cellular process implicated in the health of the cell, acting as a cytoplasmatic quality control machinery by self-eating unfunctional organelles and protein aggregates. In mammals, autophagy can participate in the clearance of intracellular pathogens from the cell, and the activity of the toll-like receptors mediates its activation. However, in fish, the modulation of autophagy by these receptors in the muscle is unknown. This study describes and characterizes autophagic modulation during the immune response of fish muscle cells after a challenge with intracellular pathogen Piscirickettsia salmonis. For this, primary cultures of muscle cells were challenged with P. salmonis, and the expressions of immune markers il-1β, tnfα, il-8, hepcidin, tlr3, tlr9, mhc-I and mhc-II were analyzed through RT-qPCR. The expressions of several genes involved in autophagy (becn1, atg9, atg5, atg12, lc3, gabarap and atg4) were also evaluated with RT-qPCR to understand the autophagic modulation during an immune response. In addition, LC3-II protein content was measured via Western blot. The challenge of trout muscle cells with P. salmonis triggered a concomitant immune response to the activation of the autophagic process, suggesting a close relationship between these two processes.
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Li, Hongli, Celien Lismont, Cláudio F. Costa, Mohamed A. F. Hussein, Myriam Baes, and Marc Fransen. "Enhanced Levels of Peroxisome-Derived H2O2 Do Not Induce Pexophagy but Impair Autophagic Flux in HEK-293 and HeLa Cells." Antioxidants 12, no. 3 (March 2, 2023): 613. http://dx.doi.org/10.3390/antiox12030613.
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Peroxisomes are functionally specialized organelles that harbor multiple hydrogen peroxide (H2O2)-producing and -degrading enzymes. Given that this oxidant functions as a major redox signaling agent, peroxisomes have the intrinsic ability to mediate and modulate H2O2-driven processes, including autophagy. However, it remains unclear whether changes in peroxisomal H2O2 (po-H2O2) emission impact the autophagic process and to which extent peroxisomes with a disturbed H2O2 metabolism are selectively eliminated through a process called “pexophagy”. To address these issues, we generated and validated HEK-293 and HeLa pexophagy reporter cell lines in which the production of po-H2O2 can be modulated. We demonstrate that (i) po-H2O2 can oxidatively modify multiple selective autophagy receptors and core autophagy proteins, (ii) neither modest nor robust levels of po-H2O2 emission act as a prime determinant of pexophagy, and (iii) high levels of po-H2O2 impair autophagic flux by oxidative inhibition of enzymes involved in LC3II formation. Unexpectedly, our analyses also revealed that the autophagy receptor optineurin can be recruited to peroxisomes, thereby triggering pexophagy. In summary, these findings lend support to the idea that, during cellular and organismal aging, peroxisomes with enhanced H2O2 release can escape pexophagy and downregulate autophagic activity, thereby perpetuating the accumulation of damaged and toxic cellular debris.
7
Papandreou, Margarita-Elena, and Nektarios Tavernarakis. "Selective Autophagy as a Potential Therapeutic Target in Age-Associated Pathologies." Metabolites 11, no. 9 (August 31, 2021): 588. http://dx.doi.org/10.3390/metabo11090588.
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Progressive accumulation of damaged cellular constituents contributes to age-related diseases. Autophagy is the main catabolic process, which recycles cellular material in a multitude of tissues and organs. Autophagy is activated upon nutrient deprivation, and oncogenic, heat or oxidative stress-induced stimuli to selectively degrade cell constituents and compartments. Specificity and accuracy of the autophagic process is maintained via the precision of interaction of autophagy receptors or adaptors and substrates by the intricate, stepwise orchestration of specialized integrating stimuli. Polymorphisms in genes regulating selective autophagy have been linked to aging and age-associated disorders. The involvement of autophagy perturbations in aging and disease indicates that pharmacological agents balancing autophagic flux may be beneficial, in these contexts. Here, we introduce the modes and mechanisms of selective autophagy, and survey recent experimental evidence of dysfunctional autophagy triggering severe pathology. We further highlight identified pharmacological targets that hold potential for developing therapeutic interventions to alleviate cellular autophagic cargo burden and associated pathologies.
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Skendros, Panagiotis, and Ioannis Mitroulis. "Host Cell Autophagy in Immune Response to Zoonotic Infections." Clinical and Developmental Immunology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/910525.
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Autophagy is a fundamental homeostatic process in which cytoplasmic targets are sequestered within double-membraned autophagosomes and subsequently delivered to lysosomes for degradation. Accumulating evidence supports the pivotal role of autophagy in host defense against intracellular pathogens implicating both innate and adaptive immunity. Many of these pathogens cause common zoonotic infections worldwide. The induction of the autophagic machinery by innate immune receptors signaling, such as TLRs, NOD1/2, and p62/SQSTM1 in antigen-presenting cells results in inhibition of survival and elimination of invading pathogens. Furthermore, Th1 cytokines induce the autophagic process, whereas autophagy also contributes to antigen processing and MHC class II presentation, linking innate to adaptive immunity. However, several pathogens have developed strategies to avoid autophagy or exploit autophagic machinery to their advantage. This paper focuses on the role of host cell autophagy in the regulation of immune response against intracellular pathogens, emphasizing on selected bacterial and protozoan zoonoses.
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Wang, Wang-sheng, Wen-jiao Li, Ya-wei Wang, Lu-yao Wang, Ya-bing Mi, Jiang-wen Lu, Yi Lu, Chu-yue Zhang, and Kang Sun. "Involvement of serum amyloid A1 in the rupture of fetal membranes through induction of collagen I degradation." Clinical Science 133, no. 3 (February 2019): 515–30. http://dx.doi.org/10.1042/cs20180950.
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Abstract The de novo synthesis of serum amyloid A1 (SAA1) is augmented in human fetal membranes at parturition. However, its role in parturition remains largely unknown. Here, we investigated whether SAA1 was involved in the rupture of fetal membranes, a crucial event in parturition accompanied with extensive degradation of collagens. Results showed that SAA1 decreased both intracellular and extracellular COL1A1 and COL1A2 abundance, the two subunits of collagen I, without affecting their mRNA levels in human amnion fibroblasts. These reductions were completely blocked only with inhibition of both matrix metalloproteases (MMPs) and autophagy. Consistently, SAA1 increased MMP-2/9 abundance and the markers for autophagic activation including autophagy related (ATG) 7 (ATG7) and the microtubule-associated protein light chain 3 β (LC3B) II/I ratio with the formation of LC3 punctas and autophagic vacuoles in the fibroblasts. Moreover, the autophagic degradation of COL1A1/COL1A2 and activation of MMP-2/9 by SAA1 were blocked by inhibitors for the toll-like receptors 2/4 (TLR2/4) or NF-κB. Finally, reciprocal corresponding changes of SAA1 and collagen I were observed in the amnion following spontaneous rupture of membranes (ROM) at parturition. Conclusively, SAA1 may participate in membrane rupture at parturition by degradating collagen I via both autophagic and MMP pathways. These effects of SAA1 appear to be mediated by the TLR2/4 receptors and the NF-κB pathway.
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Cheng, Li-sha, Jing Li, Yun Liu, Fu-ping Wang, Si-qi Wang, Wei-min She, Sheng-di Wu, Xiao-long Qi, Yong-ping Zhou, and Wei Jiang. "HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection." Clinical Science 131, no. 5 (February 15, 2017): 381–94. http://dx.doi.org/10.1042/cs20160704.
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High-mobility group box-1 (HMGB1) protein, as one of the well-known damage-associated molecular pattern molecules (DAMPs), is enriched in chronic hepatitis B virus (HBV) infection and has a context-dependent role in autophagy, a highly conserved self-digestive process in response to environmental stress. Recent mouse studies indicate that autophagy is highly active in regulatory T (Treg)-cells. In the present study, we evaluated spontaneous and induced autophagy of peripheral Treg cells from 98 patients with chronic hepatitis B (CHB), by measuring levels of lipidated form of microtubule-associated light chain 3 (LC3-II, marker for closed autophagosomes) and observing autophagic vacuoles (AV) with transmission electron microscope. No significant difference was found in spontaneous autophagy of either Treg or CD4+ naive cells when comparing CHB patients with healthy subjects, apart from CHB-Treg showed significantly higher autophagic activity after activation by anti-CD3–CD28 beads. Besides, incubation of CHB-Treg cells with CHB-serum greatly maintained their autophagic behaviour, which could be significantly diminished by blocking HMGB1 with the neutralizing antibody. Further, we characterized time- and dose-dependent effects by recombinant HMGB1 protein on autophagy of CHB-Treg cells. We also documented a significant up-regulation of HMGB1 and its receptors [toll-like receptor (TLR4), receptor for advanced glycation end-product (RAGE)] in both peripheral and intra-hepatic microenvironments of CHB patients. Moreover, the RAGE–extracellular regulated protein kinases (ERK) axis and rapamycin-sensitive components of mammalian target of rapamycin (mTOR) pathways were demonstrated in vitro to be involved in HMGB1-induced autophagy of Treg cells. Additionally, HMGB1-induced autophagy could maintain cell survival and functional stability of CHB-Treg cells. Our findings could open new perspectives in developing therapeutic strategies to activate specific anti-HBV immunity by diminishing Treg autophagy.
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LING, PIN, Kuan-Ru Chen, Chen-Chu Kao, Huai-Chia Chuang, and Tse-Hua Tan. "Emerging roles of an innate immune regulator TAPE in Toll-like receptors, RIG-I-like receptors, and beyond." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 202.35. http://dx.doi.org/10.4049/jimmunol.196.supp.202.35.
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Abstract Pattern-recognition receptors (PRRs) trigger innate immune defenses against pathogen infection via downstream signaling pathways linking to inflammation and cell-autonomous immunity like phagocytosis and autophagy. IKK family kinases, IKKα and IKKβ, function to relay PRR signals to proinflammatory cytokine production to amplify innate immune responses. TBK1, a non-canonical IKK kinase, links nucleic acid sensors to type I interferon induction against viral infection and also regulates the autophagic clearance of intracellular bacteria. TBK1-Associated Protein in Endolysosomes designated TAPE, also known as CC2D1A, is an innate immune regulator acting upstream of Trif to regulate the TLR3 and TLR4 pathways, or upstream of MAVS to regulate the cytosolic RIG-I-like receptor (RLR) pathways. To our best knowledge, TAPE is the first regulator implicated in both the endosomal TLR and cytosolic RLR pathways at such an early step. We are thus interested in investigating in vivo roles of TAPE in innate immunity and molecular mechanisms by which TAPE regulates TLRs, RLRs, and possibly other PRRs. TAPE conditional knockout (cKO) mice, in which TAPE is selectively disrupted in immune cells, have been generated for our study. Our results showed that upon influenza A virus infection, TAPE cKO mice exhibited a more severe mortality than wild type mice. Further, TAPE cKO mice were shown to be more susceptible to Salmonella Typhimurium infection but more resistant to LPS-induced septic shock. Notably, ex vivo results showed that TAPE was critical for the autophagic clearance of Salmonella Typhimurium. Together, our data support a critical role for TAPE in regulating innate immune defenses through TLRs, RLRs, and autophagy.
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Takahashi, Shun-saku, Yu-Shin Sou, Tetsuya Saito, Akiko Kuma, Takayuki Yabe, Yuki Sugiura, Hyeon-Cheol Lee, et al. "Loss of autophagy impairs physiological steatosis by accumulation of NCoR1." Life Science Alliance 3, no. 1 (December 26, 2019): e201900513. http://dx.doi.org/10.26508/lsa.201900513.
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Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, such as after a meal. LDs serve as an energy reservoir during fasting and have a buffering capacity that prevents lipotoxicity. Autophagy and the autophagic machinery have been proposed to play a role in LD biogenesis, but the underlying molecular mechanism remains unclear. Here, we show that when nuclear receptor co-repressor 1 (NCoR1), which inhibits the transactivation of nuclear receptors, accumulates because of autophagy suppression, LDs decrease in size and number. Ablation of ATG7, a gene essential for autophagy, suppressed the expression of gene targets of liver X receptor α, a nuclear receptor responsible for fatty acid and triglyceride synthesis in an NCoR1-dependent manner. LD accumulation in response to fasting and after hepatectomy was hampered by the suppression of autophagy. These results suggest that autophagy controls physiological hepatosteatosis by fine-tuning NCoR1 protein levels.
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Rogov, Vladimir V., Hironori Suzuki, Evgenij Fiskin, Philipp Wild, Andreas Kniss, Alexis Rozenknop, Ryuichi Kato, et al. "Structural basis for phosphorylation-triggered autophagic clearance of Salmonella." Biochemical Journal 454, no. 3 (August 29, 2013): 459–66. http://dx.doi.org/10.1042/bj20121907.
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Selective autophagy is mediated by the interaction of autophagy modifiers and autophagy receptors that also bind to ubiquitinated cargo. Optineurin is an autophagy receptor that plays a role in the clearance of cytosolic Salmonella. The interaction between receptors and modifiers is often relatively weak, with typical values for the dissociation constant in the low micromolar range. The interaction of optineurin with autophagy modifiers is even weaker, but can be significantly enhanced through phosphorylation by the TBK1 {TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor κB activator]-binding kinase 1}. In the present study we describe the NMR and crystal structures of the autophagy modifier LC3B (microtubule-associated protein light chain 3 beta) in complex with the LC3 interaction region of optineurin either phosphorylated or bearing phospho-mimicking mutations. The structures show that the negative charge induced by phosphorylation is recognized by the side chains of Arg11 and Lys51 in LC3B. Further mutational analysis suggests that the replacement of the canonical tryptophan residue side chain of autophagy receptors with the smaller phenylalanine side chain in optineurin significantly weakens its interaction with the autophagy modifier LC3B. Through phosphorylation of serine residues directly N-terminally located to the phenylalanine residue, the affinity is increased to the level normally seen for receptor–modifier interactions. Phosphorylation, therefore, acts as a switch for optineurin-based selective autophagy.
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Eskelinen, Eeva-Liisa, Anna Lena Illert, Yoshitaka Tanaka, Günter Schwarzmann, Judith Blanz, Kurt von Figura, and Paul Saftig. "Role of LAMP-2 in Lysosome Biogenesis and Autophagy." Molecular Biology of the Cell 13, no. 9 (September 2002): 3355–68. http://dx.doi.org/10.1091/mbc.e02-02-0114.
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In LAMP-2–deficient mice autophagic vacuoles accumulate in many tissues, including liver, pancreas, muscle, and heart. Here we extend the phenotype analysis using cultured hepatocytes. In LAMP-2–deficient hepatocytes the half-life of both early and late autophagic vacuoles was prolonged as evaluated by quantitative electron microscopy. However, an endocytic tracer reached the autophagic vacuoles, indicating delivery of endo/lysosomal constituents to autophagic vacuoles. Enzyme activity measurements showed that the trafficking of some lysosomal enzymes to lysosomes was impaired. Immunoprecipitation of metabolically labeled cathepsin D indicated reduced intracellular retention and processing in the knockout cells. The steady-state level of 300-kDa mannose 6-phosphate receptor was slightly lower in LAMP-2–deficient hepatocytes, whereas that of 46-kDa mannose 6-phosphate receptor was decreased to 30% of controls due to a shorter half-life. Less receptor was found in the Golgi region and in vesicles and tubules surrounding multivesicular endosomes, suggesting impaired recycling from endosomes to the Golgi. More receptor was found in autophagic vacuoles, which may explain its shorter half-life. Our data indicate that in hepatocytes LAMP-2 deficiency either directly or indirectly leads to impaired recycling of 46-kDa mannose 6-phosphate receptors and partial mistargeting of a subset of lysosomal enzymes. Autophagic vacuoles may accumulate due to impaired capacity for lysosomal degradation.
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Kohno, Shohei, Yuji Shiozaki, Audrey L. Keenan, Shinobu Miyazaki-Anzai, and Makoto Miyazaki. "An N-terminal–truncated isoform of FAM134B (FAM134B-2) regulates starvation-induced hepatic selective ER-phagy." Life Science Alliance 2, no. 3 (May 17, 2019): e201900340. http://dx.doi.org/10.26508/lsa.201900340.
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Autophagy is a conserved system that adapts to nutrient starvation, after which proteins and organelles are degraded to recycle amino acids in response to starvation. Recently, the ER was added to the list of targets of autophagic degradation. Autophagic degradation pathways of bulk ER and the specific proteins sorted through the ER are considered key mechanisms in maintaining ER homeostasis. Four ER-resident proteins (FAM134B, CCPG1, SEC62, and RTN3) have been identified as ER-resident cargo receptors, which contain LC3-interacting regions. In this study, we identified an N-terminal–truncated isoform of FAM134B (FAM134B-2) that contributes to starvation-induced ER-related autophagy. Hepatic FAM134B-2 but not full-length FAM134B (FAM134B-1) is expressed in a fed state. Starvation drastically induces FAM134B-2 but no other ER-resident cargo receptors through transcriptional activation by C/EBPβ. C/EBPβ overexpression increases FAM134B-2 recruitment into autophagosomes and lysosomal degradation. FAM134B-2 regulates lysosomal degradation of ER-retained secretory proteins such as ApoCIII. This study demonstrates that the C/EBPβ-FAM134B-2 axis regulates starvation-induced selective ER-phagy.
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Mejlvang, Jakob, Hallvard Olsvik, Steingrim Svenning, Jack-Ansgar Bruun, Yakubu Princely Abudu, Kenneth Bowitz Larsen, Andreas Brech, et al. "Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy." Journal of Cell Biology 217, no. 10 (July 17, 2018): 3640–55. http://dx.doi.org/10.1083/jcb.201711002.
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It is not clear to what extent starvation-induced autophagy affects the proteome on a global scale and whether it is selective. In this study, we report based on quantitative proteomics that cells during the first 4 h of acute starvation elicit lysosomal degradation of up to 2–3% of the proteome. The most significant changes are caused by an immediate autophagic response elicited by shortage of amino acids but executed independently of mechanistic target of rapamycin and macroautophagy. Intriguingly, the autophagy receptors p62/SQSTM1, NBR1, TAX1BP1, NDP52, and NCOA4 are among the most efficiently degraded substrates. Already 1 h after induction of starvation, they are rapidly degraded by a process that selectively delivers autophagy receptors to vesicles inside late endosomes/multivesicular bodies depending on the endosomal sorting complex required for transport III (ESCRT-III). Our data support a model in which amino acid deprivation elicits endocytosis of specific membrane receptors, induction of macroautophagy, and rapid degradation of autophagy receptors by endosomal microautophagy.
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Shrestha, Birendra Kumar, Mads Skytte Rasmussen, Yakubu Princely Abudu, Jack-Ansgar Bruun, Kenneth Bowitz Larsen, Endalkachew A. Alemu, Eva Sjøttem, Trond Lamark, and Terje Johansen. "NIMA-related kinase 9–mediated phosphorylation of the microtubule-associated LC3B protein at Thr-50 suppresses selective autophagy of p62/sequestosome 1." Journal of Biological Chemistry 295, no. 5 (December 19, 2019): 1240–60. http://dx.doi.org/10.1074/jbc.ra119.010068.
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Human ATG8 family proteins (ATG8s) are active in all steps of the macroautophagy pathway, and their lipidation is essential for autophagosome formation. Lipidated ATG8s anchored to the outer surface of the phagophore serve as scaffolds for binding of other core autophagy proteins and various effector proteins involved in trafficking or fusion events, whereas those at the inner surface are needed for assembly of selective autophagy substrates. Their scaffolding role depends on specific interactions between the LC3-interacting region (LIR) docking site (LDS) in ATG8s and LIR motifs in various interaction partners. LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro. A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). NEK9 knockdown or knockout enhanced degradation of the autophagy receptor and substrate p62. Of note, the suppression of p62 degradation was mediated by NEK9-mediated phosphorylation of LC3B Thr-50. Consistently, reconstitution of LC3B-KO cells with the phospho-mimicking T50E variant inhibited autophagic p62 degradation. PKCζ knockdown did not affect autophagic p62 degradation, whereas STK3/4 knockouts inhibited autophagic p62 degradation independently of LC3B Thr-50 phosphorylation. Our findings suggest that NEK9 suppresses LC3B-mediated autophagy of p62 by phosphorylating Thr-50 within the LDS of LC3B.
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Acheampong, Atiako Kwame, Carly Shanks, Chia-Yi Cheng, G. Eric Schaller, Yasin Dagdas, and Joseph J. Kieber. "EXO70D isoforms mediate selective autophagic degradation of type-A ARR proteins to regulate cytokinin sensitivity." Proceedings of the National Academy of Sciences 117, no. 43 (October 13, 2020): 27034–43. http://dx.doi.org/10.1073/pnas.2013161117.
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The phytohormone cytokinin influences many aspects of plant growth and development, several of which also involve the cellular process of autophagy, including leaf senescence, nutrient remobilization, and developmental transitions. The Arabidopsis type-A response regulators (type-A ARR) are negative regulators of cytokinin signaling that are transcriptionally induced in response to cytokinin. Here, we describe a mechanistic link between cytokinin signaling and autophagy, demonstrating that plants modulate cytokinin sensitivity through autophagic regulation of type-A ARR proteins. Type-A ARR proteins were degraded by autophagy in an AUTOPHAGY-RELATED (ATG)5-dependent manner, and this degradation is promoted by phosphorylation on a conserved aspartate in the receiver domain of the type-A ARRs. EXO70D family members interacted with type-A ARR proteins, likely in a phosphorylation-dependent manner, and recruited them to autophagosomes via interaction of the EXO70D AIM with the core autophagy protein, ATG8. Consistently, loss-of-function exo70D1,2,3 mutants exhibited compromised targeting of type-A ARRs to autophagic vesicles, have elevated levels of type-A ARR proteins, and are hyposensitive to cytokinin. Disruption of both type-A ARRs and EXO70D1,2,3 compromised survival in carbon-deficient conditions, suggesting interaction between autophagy and cytokinin responsiveness in response to stress. These results indicate that the EXO70D proteins act as selective autophagy receptors to target type-A ARR cargos for autophagic degradation, demonstrating modulation of cytokinin signaling by selective autophagy.
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Morleo, Manuela, and Brunella Franco. "The OFD1 protein is a novel player in selective autophagy: another tile to the cilia/autophagy puzzle." Cell Stress 5, no. 3 (March 8, 2021): 33–36. http://dx.doi.org/10.15698/cst2021.03.244.
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The autophagy-lysosomal pathway is one of the main degradative routes which cells use to balance sources of energy. A number of proteins orchestrate the formation of autophagosomes, membranous organelles instrumental in autophagy. Selective autophagy, involving the recognition and removal of specific targets, is mediated by autophagy receptors, which recognize cargos and the autophagosomal membrane protein LC3 for lysosomal degradation. Recently, bidirectional crosstalk has emerged between autophagy and primary cilia, microtubule-based sensory organelles extending from cells and anchored by the basal body, derived from the mother centriole of the centrosome. The molecular mechanisms underlying the direct role of autophagic proteins in cilia biology and, conversely, the impact of this organelle in autophagy remains elusive. Recently, we uncovered the molecular mechanism by which the centrosomal/basal body protein OFD1 controls the LC3-mediated autophagic cascade. In particular, we demonstrated that OFD1 acts as a selective autophagy receptor by regulating the turnover of unc-51-like kinase (ULK1) complex, which plays a crucial role in the initiation steps of autophagosome biogenesis. Moreover, we showed that patients with a genetic condition caused by mutations in OFD1 and associated with cilia dysfunction, display excessive autophagy and we demonstrated that autophagy inhibition significantly ameliorates the renal cystic phenotype in a conditional mouse model recapitulating the features of the disease (Morleo et al. 2020, EMBO J, doi: 10.15252/embj.2020105120). We speculate that abnormal autophagy may underlie some of the clinical manifestations observed in the disorders ascribed to cilia dysfunction.
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Ran, Jie, Sayed M. Hashimi, and Jian-Zhong Liu. "Emerging Roles of the Selective Autophagy in Plant Immunity and Stress Tolerance." International Journal of Molecular Sciences 21, no. 17 (August 31, 2020): 6321. http://dx.doi.org/10.3390/ijms21176321.
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Autophagy is a conserved recycling system required for cellular homeostasis. Identifications of diverse selective receptors/adaptors that recruit appropriate autophagic cargoes have revealed critical roles of selective autophagy in different biological processes in plants. In this review, we summarize the emerging roles of selective autophagy in both biotic and abiotic stress tolerance and highlight the new features of selective receptors/adaptors and their interactions with both the cargoes and Autophagy-related gene 8s (ATG8s). In addition, we review how the two major degradation systems, namely the ubiquitin–proteasome system (UPS) and selective autophagy, are coordinated to cope with stress in plants. We especially emphasize how plants develop the selective autophagy as a weapon to fight against pathogens and how adapted pathogens have evolved the strategies to counter and/or subvert the immunity mediated by selective autophagy.
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Waters, Sarah L., Katie Marchbank, Ellen Solomon, and Caroline A. Whitehouse. "Autophagic receptors Nbr1 and p62 coregulate skeletal remodelling." Autophagy 6, no. 7 (October 2010): 981–83. http://dx.doi.org/10.4161/auto.6.7.13155.
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Richter, Benjamin, Danielle A. Sliter, Lina Herhaus, Alexandra Stolz, Chunxin Wang, Petra Beli, Gabriele Zaffagnini, et al. "Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria." Proceedings of the National Academy of Sciences 113, no. 15 (March 30, 2016): 4039–44. http://dx.doi.org/10.1073/pnas.1523926113.
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Selective autophagy of damaged mitochondria requires autophagy receptors optineurin (OPTN), NDP52 (CALCOCO2), TAX1BP1, and p62 (SQSTM1) linking ubiquitinated cargo to autophagic membranes. By using quantitative proteomics, we show that Tank-binding kinase 1 (TBK1) phosphorylates all four receptors on several autophagy-relevant sites, including the ubiquitin- and LC3-binding domains of OPTN and p62/SQSTM1 as well as the SKICH domains of NDP52 and TAX1BP1. Constitutive interaction of TBK1 with OPTN and the ability of OPTN to bind to ubiquitin chains are essential for TBK1 recruitment and kinase activation on mitochondria. TBK1 in turn phosphorylates OPTN’s UBAN domain at S473, thereby expanding the binding capacity of OPTN to diverse Ub chains. In combination with phosphorylation of S177 and S513, this posttranslational modification promotes recruitment and retention of OPTN/TBK1 on ubiquitinated, damaged mitochondria. Moreover, phosphorylation of OPTN on S473 enables binding to pS65 Ub chains and is also implicated in PINK1-driven and Parkin-independent mitophagy. Thus, TBK1-mediated phosphorylation of autophagy receptors creates a signal amplification loop operating in selective autophagy of damaged mitochondria.
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Du, Chunyang, Tao Zhang, Xia Xiao, Yonghong Shi, Huijun Duan, and Yunzhuo Ren. "Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway." Biochemical Journal 474, no. 16 (August 2, 2017): 2733–47. http://dx.doi.org/10.1042/bcj20170272.
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Protease-activated receptor-2 (PAR2), which belongs to a specific class of the G-protein-coupled receptors, is central to several inflammation processes. However, the precise molecular mechanism involved remains undefined. Autophagy has been previously shown to affect inflammation. In the present study, we examine the effect of PAR2 on kidney tubular epithelial autophagy and on autophagy-related inflammation and reveal the underlying mechanism involved. Autophagic activity and levels of autophagic marker LC3 were examined in human kidney tubular epithelial cells with PAR2 knockdown or overexpression. We administered the mammalian target of rapamycin (mTOR) inhibitor (rapamycin) or activator (MHY1485) to investigate the function of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway. We also used transforming growth factor-β1 (TGF-β1)-induced HK-2 cell inflammation models to investigate the role of PAR2-associated autophagy in kidney tubular epithelial inflammation. PAR2 antagonist and rapamycin were administered to mice after unilateral ureteral obstruction to detect the correlations between PAR2, autophagy, and inflammation. Our results show that PAR2 overexpression in HK-2 cells led to a greater reduction in autophagy via the PI3K/Akt/mTOR pathway activation and induces autophagy-related inflammation. Meanwhile, a knockdown of PAR2 via PAR2 RNAi transfection greatly increased autophagy and alleviated autophagy-associated inflammation. In unilateral ureteral obstruction (UUO) kidneys, PAR2 antagonist treatment greatly attenuated renal inflammation and interstitial injury by enhancing autophagy. Moreover, inhibition of mTOR, rapa, markedly increased autophagy and inhibited the UUO-induced inflammation. We conclude that PAR2 induces kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway. Our results are suggestive that PAR2 inhibition may play a role in the treatment of diseases with increased inflammatory responses in renal systems.
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Kim, Yi Sak, Prashanta Silwal, Soo Yeon Kim, Tamotsu Yoshimori, and Eun-Kyeong Jo. "Autophagy-activating strategies to promote innate defense against mycobacteria." Experimental & Molecular Medicine 51, no. 12 (December 2019): 1–10. http://dx.doi.org/10.1038/s12276-019-0290-7.
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AbstractMycobacterium tuberculosis (Mtb) is a major causal pathogen of human tuberculosis (TB), which is a serious health burden worldwide. The demand for the development of an innovative therapeutic strategy to treat TB is high due to drug-resistant forms of TB. Autophagy is a cell-autonomous host defense mechanism by which intracytoplasmic cargos can be delivered and then destroyed in lysosomes. Previous studies have reported that autophagy-activating agents and small molecules may be beneficial in restricting intracellular Mtb infection, even with multidrug-resistant Mtb strains. Recent studies have revealed the essential roles of host nuclear receptors (NRs) in the activation of the host defense through antibacterial autophagy against Mtb infection. In particular, we discuss the function of estrogen-related receptor (ERR) α and peroxisome proliferator-activated receptor (PPAR) α in autophagy regulation to improve host defenses against Mtb infection. Despite promising findings relating to the antitubercular effects of various agents, our understanding of the molecular mechanism by which autophagy-activating agents suppress intracellular Mtb in vitro and in vivo is lacking. An improved understanding of the antibacterial autophagic mechanisms in the innate host defense will eventually lead to the development of new therapeutic strategies for human TB.
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Liu, Elizabeth, Yalitza Lopez Corcino, Jose-Andres C. Portillo, Yanling Miao, and Carlos S. Subauste. "Identification of Signaling Pathways by Which CD40 Stimulates Autophagy and Antimicrobial Activity against Toxoplasma gondii in Macrophages." Infection and Immunity 84, no. 9 (June 27, 2016): 2616–26. http://dx.doi.org/10.1128/iai.00101-16.
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CD40 is an important stimulator of autophagy and autophagic killing ofToxoplasma gondiiin host cells. In contrast to autophagy induced by nutrient deprivation or pattern recognition receptors, less is known about the effects of cell-mediated immunity on Beclin 1 and ULK1, key regulators of autophagy. Here we studied the molecular mechanisms by which CD40 stimulates autophagy in macrophages. CD40 ligation caused biphasic Jun N-terminal protein kinase (JNK) phosphorylation. The second phase of JNK phosphorylation was dependent on autocrine production of tumor necrosis factor alpha (TNF-α). TNF-α and JNK signaling were required for the CD40-induced increase in autophagy. JNK signaling downstream of CD40 caused Ser-87 phosphorylation of Bcl-2 and dissociation between Bcl-2 and Beclin 1, an event known to stimulate the autophagic function of Beclin 1. However, TNF-α alone was unable to stimulate autophagy. CD40 also stimulated autophagy via a pathway that included calcium/calmodulin-dependent kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), and ULK1. CD40 caused AMPK phosphorylation at its activating site, Thr-172. This effect was mediated by CaMKKβ and was not impaired by neutralization of TNF-α. CD40 triggered AMPK-dependent Ser-555 phosphorylation of ULK1. CaMKKβ, AMPK, and ULK1 were required for CD40-induced increase in autophagy. CD40-mediated autophagic killing ofToxoplasma gondiiis known to require TNF-α. Knockdown of JNK, CaMKKβ, AMPK, or ULK1 preventedT. gondiikilling in CD40-activated macrophages. The second phase of JNK phosphorylation—Bcl-2 phosphorylation—Bcl-2–Beclin 1 dissociation and AMPK phosphorylation-ULK1 phosphorylation occurred simultaneously at ∼4 h post-CD40 stimulation. Thus, CaMKKβ and TNF-α are upstream molecules by which CD40 acts on ULK1 and Beclin 1 to stimulate autophagy and killing ofT. gondii.
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Jain, Moon, Prasanna K. Sahu, and Kashif Hanif. "Involvement of angiotensin II and beta-adrenergic receptors in the regulation of autophagy in human endothelial EA.hy926 cell line." Tropical Journal of Pharmaceutical Research 19, no. 4 (May 14, 2020): 751–57. http://dx.doi.org/10.4314/tjpr.v19i4.11.
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Purpose: To investigate the role of angiotensin II (Ang II) and β adrenergic receptors (βARs) in autophagy regulation in human endothelial EA.hy926 cell line.Methods: The effect of pharmacological modulation of Ang II receptors and βARs on the expression of LC3B-II and p62 proteins (autophagosome formation marker and autophagic flux marker, respectively) in the human endothelial EA.hy926 cell line were investigated by immunoblotting technique.Results: Ang II-induced autophagy was characterized by increased LC3B-II and reduced p62 expressions. Candesartan, an AT1R agonist, significantly suppressed the effects of Ang II, while a selective AT2R antagonist, PD123319, inhibited the effect of candesartan. An AT2R agonist, CGP-42112A, also suppressed the Ang II-induced autophagy. Treatment with isoproterenol enhanced the expression of LC3B-II and reduced that of p62; these effects were suppressed upon cotreatment with propranolol (non-selective βAR blocker propranolol). A selective β1AR agonist, dobutamine, reduced the expression of LC3B-II, and increased that of p62; the same was suppressed upon treatment with a selective β1AR antagonist, metoprolol. A selective β2AR agonist, salbutamol, resulted in increased expression of LC3B-II and reduced expression of p62. These effects were encountered upon treatment with selective β2AR antagonist, ICI-118,551.Conclusion: Based on the foregoing, it is evident that AT1Rs mediates Ang II-induced endothelial cell autophagy, while AT2Rs antagonizes the mechanism. βAR activation mediates isoproterenol-induced endothelial cell autophagy, which results from the balance of β1ARs-mediated suppression and β2ARsmediated upregulation of autophagy in the endothelial cells.
Keywords: Autophagy, Angiotensin II type 1 receptors, Angiotensin II type 2 receptors β adrenergic type 1 receptors, β adrenergic type 2 receptors endothelial cells
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Navarro-Lérida, Inmaculada, Anna M. Aragay, Alejandro Asensio, and Catalina Ribas. "Gq Signaling in Autophagy Control: Between Chemical and Mechanical Cues." Antioxidants 11, no. 8 (August 18, 2022): 1599. http://dx.doi.org/10.3390/antiox11081599.
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All processes in human physiology relies on homeostatic mechanisms which require the activation of specific control circuits to adapt the changes imposed by external stimuli. One of the critical modulators of homeostatic balance is autophagy, a catabolic process that is responsible of the destruction of long-lived proteins and organelles through a lysosome degradative pathway. Identification of the mechanism underlying autophagic flux is considered of great importance as both protective and detrimental functions are linked with deregulated autophagy. At the mechanistic and regulatory levels, autophagy is activated in response to diverse stress conditions (food deprivation, hyperthermia and hypoxia), even a novel perspective highlight the potential role of physical forces in autophagy modulation. To understand the crosstalk between all these controlling mechanisms could give us new clues about the specific contribution of autophagy in a wide range of diseases including vascular disorders, inflammation and cancer. Of note, any homeostatic control critically depends in at least two additional and poorly studied interdependent components: a receptor and its downstream effectors. Addressing the selective receptors involved in autophagy regulation is an open question and represents a new area of research in this field. G-protein coupled receptors (GPCRs) represent one of the largest and druggable targets membrane receptor protein superfamily. By exerting their action through G proteins, GPCRs play fundamental roles in the control of cellular homeostasis. Novel studies have shown Gαq, a subunit of heterotrimeric G proteins, as a core modulator of mTORC1 and autophagy, suggesting a fundamental contribution of Gαq-coupled GPCRs mechanisms in the control of this homeostatic feedback loop. To address how GPCR-G proteins machinery integrates the response to different stresses including oxidative conditions and mechanical stimuli, could provide deeper insight into new signaling pathways and open potential and novel therapeutic strategies in the modulation of different pathological conditions.
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van Niekerk, Gustav, Ashwin W. Isaacs, Theo Nell, and Anna-Mart Engelbrecht. "Sickness-Associated Anorexia: Mother Nature’s Idea of Immunonutrition?" Mediators of Inflammation 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/8071539.
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During an infection, expansion of immune cells, assembly of antibodies, and the induction of a febrile response collectively place continual metabolic strain on the host. These considerations also provide a rationale for nutritional support in critically ill patients. Yet, results from clinical and preclinical studies indicate that aggressive nutritional support does not always benefit patients and may occasionally be detrimental. Moreover, both vertebrates and invertebrates exhibit a decrease in appetite during an infection, indicating that such sickness-associated anorexia (SAA) is evolutionarily conserved. It also suggests that SAA performs a vital function during an infection. We review evidence signifying that SAA may present a mechanism by which autophagic flux is upregulated systemically. A decrease in serum amino acids during an infection promotes autophagy not only in immune cells, but also in nonimmune cells. Similarly, bile acids reabsorbed postprandially inhibit hepatic autophagy by binding to farnesoid X receptors, indicating that SAA may be an attempt to conserve autophagy. In addition, augmented autophagic responses may play a critical role in clearing pathogens (xenophagy), in the presentation of epitopes in nonprovisional antigen presenting cells and the removal of damaged proteins and organelles. Collectively, these observations suggest that some patients might benefit from permissive underfeeding.
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Niso, Mauro, Joanna Kopecka, Francesca Serena Abatematteo, Francesco Berardi, Chiara Riganti, and Carmen Abate. "Multifunctional thiosemicarbazones targeting sigma receptors: in vitro and in vivo antitumor activities in pancreatic cancer models." Cellular Oncology 44, no. 6 (September 29, 2021): 1307–23. http://dx.doi.org/10.1007/s13402-021-00638-5.
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Abstract Purpose Association of the metal chelating portion of thiosemicarbazone with the cytotoxic activity of sigma-2 receptors appears a promising strategy for the treatment of pancreatic tumors. Here, we developed a novel sigma-2 receptor targeting thiosemicarbazone (FA4) that incorporates a moiety associated with lysosome destabilization and ROS increase in order to design more efficient antitumor agents. Methods The density of sigma receptors in pancreatic cancer cells was evaluated by flow cytometry. In these cells, cytotoxicity (MTT assay) and activation of ER- and mitochondria-dependent cell death pathways (mRNA expression of GRP78, ATF6, IRE1, PERK; ROS levels by MitoSOX and DCFDA-AM; JC-1 staining) induced by the thiosemicarbazones FA4, MLP44, PS3 and ACthio-1, were evaluated. The expression of autophagic proteins (ATG5, ATG7, ATG12, beclin, p62 and LC3-I) was also studied. In addition, the in vivo effect of FA4 in xenograft models with and without gemcitabine challenge was investigated. Results We found that FA4 exerted a more potent cytotoxicity than previously studied thiosemicarbazones (MLP44, PS3 and ACthio-1), which were found to display variable effects on the ER or the mitochondria-dependent pro-apoptotic axis. By contrast, FA4 activated pro-apoptotic pathways and decreased autophagy, except in MiaPaCa2 cells, in which autophagic proteins were expressed at lower levels and remained unmodified by FA4. FA4 treatment of PANC-1 xenografted mouse models, poorly responsive to conventional chemotherapy, significantly reduced tumor volumes and increased intratumor apoptosis compared to gemcitabine, with no signs of toxicity. Conclusions Our data indicate that FA4 exhibits encouraging activity in pancreatic cancer cells unresponsive to gemcitabine. These results warrant further investigation in patient-derived pancreatic cancers, and hold promise for the development of therapies that can more efficiently target the specific characteristics of individual tumor types.
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Furuta, Nobumichi, Naonobu Fujita, Takeshi Noda, Tamotsu Yoshimori, and Atsuo Amano. "Combinational Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor Proteins VAMP8 and Vti1b Mediate Fusion of Antimicrobial and Canonical Autophagosomes with Lysosomes." Molecular Biology of the Cell 21, no. 6 (March 15, 2010): 1001–10. http://dx.doi.org/10.1091/mbc.e09-08-0693.
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Autophagy plays a crucial role in host defense, termed antimicrobial autophagy (xenophagy), as it functions to degrade intracellular foreign microbial invaders such as group A Streptococcus (GAS). Xenophagosomes undergo a stepwise maturation process consisting of a fusion event with lysosomes, after which the cargoes are degraded. However, the molecular mechanism underlying xenophagosome/lysosome fusion remains unclear. We examined the involvement of endocytic soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) in xenophagosome/lysosome fusion. Confocal microscopic analysis showed that SNAREs, including vesicle-associated membrane protein (VAMP)7, VAMP8, and vesicle transport through interaction with t-SNAREs homologue 1B (Vti1b), colocalized with green fluorescent protein-LC3 in xenophagosomes. Knockdown of Vti1b and VAMP8 with small interfering RNAs disturbed the colocalization of LC3 with lysosomal membrane protein (LAMP)1. The invasive efficiency of GAS into cells was not altered by knockdown of VAMP8 or Vti1b, whereas cellular bactericidal efficiency was significantly diminished, indicating that antimicrobial autophagy was functionally impaired. Knockdown of Vti1b and VAMP8 also disturbed colocalization of LC3 with LAMP1 in canonical autophagy, in which LC3-II proteins were negligibly degraded. In contrast, knockdown of Syntaxin 7 and Syntaxin 8 showed little effect on the autophagic fusion event. These findings strongly suggest that the combinational SNARE proteins VAMP8 and Vti1b mediate the fusion of antimicrobial and canonical autophagosomes with lysosomes, an essential event for autophagic degradation.
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Zientara-Rytter, Katarzyna, and Suresh Subramani. "The Roles of Ubiquitin-Binding Protein Shuttles in the Degradative Fate of Ubiquitinated Proteins in the Ubiquitin-Proteasome System and Autophagy." Cells 8, no. 1 (January 10, 2019): 40. http://dx.doi.org/10.3390/cells8010040.
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The ubiquitin-proteasome system (UPS) and autophagy are the two major intracellular protein quality control (PQC) pathways that are responsible for cellular proteostasis (homeostasis of the proteome) by ensuring the timely degradation of misfolded, damaged, and unwanted proteins. Ubiquitination serves as the degradation signal in both these systems, but substrates are precisely targeted to one or the other pathway. Determining how and when cells target specific proteins to these two alternative PQC pathways and control the crosstalk between them are topics of considerable interest. The ubiquitin (Ub) recognition code based on the type of Ub-linked chains on substrate proteins was believed to play a pivotal role in this process, but an increasing body of evidence indicates that the PQC pathway choice is also made based on other criteria. These include the oligomeric state of the Ub-binding protein shuttles, their conformation, protein modifications, and the presence of motifs that interact with ATG8/LC3/GABARAP (autophagy-related protein 8/microtubule-associated protein 1A/1B-light chain 3/GABA type A receptor-associated protein) protein family members. In this review, we summarize the current knowledge regarding the Ub recognition code that is bound by Ub-binding proteasomal and autophagic receptors. We also discuss how cells can modify substrate fate by modulating the structure, conformation, and physical properties of these receptors to affect their shuttling between both degradation pathways.
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Noda, Toru, Mary L. Bronson, Shang-Ming Yu, and Marilyn G. Farquhar. "The 215 KD mannose-6-phosphate receptor is involved in crinophagy but not in autophagy." Proceedings, annual meeting, Electron Microscopy Society of America 48, no. 3 (August 12, 1990): 932–33. http://dx.doi.org/10.1017/s0424820100162223.
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Autophagy and crinophagy represent the two major pathways for digestion of intracellular material via lysosomes have been described. Though both phenomena involve in corporation of cell organelles into lysosomes and thus degradation by lysosomal enzymes, the process by which autophagic and crinophagic vacuoles acquire lysosomal enzymes remains to be clarified. The aim of this work is to find out if mannose-6-phosphate (M6P) receptors are involved in this process. As a typical working model, we used hepatocytes of leupeptin-treated rats for autophagy (Fig. 1) and mammotrophs of female rats treated with estradiol for 6 days, for crinophagy. To localize the M6P receptor and lysosomal proteins, we carried out immunocytochemistry, using a immunoperoxidase pre-embedding technique and immunogold labeling on ultrathin frozen sections.Many autophagosomes induced by leupeptin treatment contained recognizable mitochondria and rough ER. The configuration and fine structure of these organelles are gradually lost and the contents of the vacuoles become more homogeneous and electron-dense, suggesting that partial digestion of the contents of autophagosomes still occurs after leupept in treatment.
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Trapannone, Riccardo, Julia Romanov, and Sascha Martens. "p62 and NBR1 functions are dispensable for aggrephagy in mouse ESCs and ESC-derived neurons." Life Science Alliance 6, no. 11 (August 24, 2023): e202301936. http://dx.doi.org/10.26508/lsa.202301936.
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Accumulation of protein aggregates is a hallmark of various neurodegenerative diseases. Selective autophagy mediates the delivery of specific cytoplasmic cargo material into lysosomes for degradation. In aggrephagy, which is the selective autophagy of protein aggregates, the cargo receptors p62 and NBR1 were shown to play important roles in cargo selection. They bind ubiquitinated cargo material via their ubiquitin-associated domains and tether it to autophagic membranes via their LC3-interacting regions. We used mouse embryonic stem cells (ESCs) in combination with genome editing to obtain further insights into the roles of p62 and NBR1 in aggrephagy. Unexpectedly, our data reveal that both ESCs and ESC-derived neurons do not show strong defects in the clearance of protein aggregates upon knockout of p62 or NBR1 and upon mutation of the p62 ubiquitin-associated domain and the LC3-interacting region motif. Taken together, our results show a robust aggregate clearance in ESCs and ESC-derived neurons. Thus, redundancy between the cargo receptors, other factors, and pathways, such as the ubiquitin-proteasome system, may compensate for the loss of function of p62 and NBR1.
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Ding, Wen-Xing, and Xiao-Ming Yin. "Mitophagy: mechanisms, pathophysiological roles, and analysis." Biological Chemistry 393, no. 7 (July 1, 2012): 547–64. http://dx.doi.org/10.1515/hsz-2012-0119.
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Abstract Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy.
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Christ, Maximilian, Heike Huesmann, Heike Nagel, Andreas Kern, and Christian Behl. "Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo." Cells 8, no. 3 (March 2, 2019): 211. http://dx.doi.org/10.3390/cells8030211.
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Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer’s disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration.
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Liang, Jin Rui, Emily Lingeman, Saba Ahmed, and Jacob E. Corn. "Atlastins remodel the endoplasmic reticulum for selective autophagy." Journal of Cell Biology 217, no. 10 (August 24, 2018): 3354–67. http://dx.doi.org/10.1083/jcb.201804185.
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Specific receptors are required for the autophagic degradation of endoplasmic reticulum (ER), known as ER-phagy. However, little is known about how the ER is remodeled and separated for packaging into autophagosomes. We developed two ER-phagy–specific reporter systems and found that Atlastins are key positive effectors and also targets of ER-phagy. Atlastins are ER-resident GTPases involved in ER membrane morphology, and Atlastin-depleted cells have decreased ER-phagy under starvation conditions. Atlastin’s role in ER-phagy requires a functional GTPase domain and proper ER localization, both of which are also involved in ER architecture. The three Atlastin family members functionally compensate for one another during ER-phagy and may form heteromeric complexes with one another. We further find that Atlastins act downstream of the FAM134B ER-phagy receptor, such that depletion of Atlastins represses ER-autophagy induced by the overexpression of FAM134B. We propose that during ER-phagy, Atlastins remodel ER membrane to separate pieces of FAM134B-marked ER for efficient autophagosomal engulfment.
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Tan, Tao, Marcel Zimmermann, and Andreas S. Reichert. "Controlling quality and amount of mitochondria by mitophagy: insights into the role of ubiquitination and deubiquitination." Biological Chemistry 397, no. 7 (July 1, 2016): 637–47. http://dx.doi.org/10.1515/hsz-2016-0125.
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Abstract Mitophagy is a selective autophagy pathway conserved in eukaryotes and plays an essential role in mitochondrial quality and quantity control. Mitochondrial fission and fusion cycles maintain a certain amount of healthy mitochondria and allow the isolation of damaged mitochondria for their elimination by mitophagy. Mitophagy can be classified into receptor-dependent and ubiquitin-dependent pathways. The mitochondrial outer membrane protein Atg32 is identified as the only known receptor for mitophagy in baker’s yeast, whereas mitochondrial proteins FUNDC1, NIX/BNIP3L, BNIP3 and Bcl2L13 are recognized as mitophagy receptors in mammalian cells. Earlier studies showed that ubiquitination and deubiquitination occurs in yeast, yet there is no direct evidence for an ubiquitin-dependent mitophagy pathway in this organism. In contrast, a ubiquitin-/PINK1-/Parkin-dependent mitophagy pathway was unraveled and was extensively characterized in mammals in recent years. Recently, a quantitative method termed synthetic quantitative array (SQA) technology was developed to identify modulators of mitophagy in baker’s yeast on a genome-wide level. The Ubp3-Bre5 deubiquitination complex was found as a negative regulator of mitophagy while promoting other autophagic pathways. Here we discuss how ubiquitination and deubiquitination regulates mitophagy and other selective forms of autophagy and what argues for using baker’s yeast as a model to study the ubiquitin-dependent mitophagy pathway.
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Prick, Tanja, Michael Thumm, Karl Köhrer, Dieter Häussinger, and Stephan Vom Dahl. "In yeast, loss of Hog1 leads to osmosensitivity of autophagy." Biochemical Journal 394, no. 1 (January 27, 2006): 153–61. http://dx.doi.org/10.1042/bj20051243.
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In mammalian liver, proteolysis is regulated by the cellular hydration state in a microtubule- and p38MAPK (p38 mitogen-activated protein kinase)-dependent fashion. Osmosensing in liver cells towards proteolysis is achieved by activation of integrin receptors. The yeast orthologue of p38MAPK is Hog1 (high-osmolarity glycerol 1), which is involved in the hyperosmotic-response pathway. Since it is not known whether starvation-induced autophagy in yeast is osmosensitive and whether Hog1 is involved in this process, we performed fluorescence microscopy experiments. The hog1Δ cells exhibited a visible decrease of autophagy in hypo-osmotic and hyperosmotic nitrogen-starvation medium as compared with normo-osmolarity, as determined by GFP (green fluorescent protein)–Atg8 (autophagy-related 8) fluorescence. Western blot analysis of GFP–Atg8 degradation showed that WT (wild-type) cells maintained a stable autophagic activity over a broad osmolarity range, whereas hog1Δ cells showed an impaired autophagic actitivity during hypo- and hyper-osmotic stress. In [3H]leucine-pre-labelled yeast cells, the proteolysis rate was osmodependent only in hog1Δ cells. Neither maturation of pro-aminopeptidase I nor vitality was affected by osmotic stress in either yeast strain. In contrast, rapamycin-dependent autophagy, as measured by degradation of GFP–Atg8, did not significantly respond to hypo-osmotic or hyperosmotic stress in hog1Δ or WT cells. We conclude that Hog1 plays a role in the stabilization machinery of nitrogen-deprivation-induced autophagy in yeast cells during ambient osmolarity changes. This could be an analogy to the p38MAPK pathway in mammalian liver, where osmosensing towards p38MAPK is required for autophagy regulation by hypo-osmotic or amino-acid-induced cell swelling. A phenotypic difference is observed in rapamycin-induced autophagy, which does not seem to respond to extracellular osmolarity changes in hog1Δ cells.
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Vural, Ali, and John H. Kehrl. "Autophagy in Macrophages: Impacting Inflammation and Bacterial Infection." Scientifica 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/825463.
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Macrophages are on the front line of host defense. They possess an array of germline-encoded pattern recognition receptors/sensors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and which activate downstream effectors/pathways to help mediate innate immune responses and host defense. Innate immune responses include the rapid induction of transcriptional networks that trigger the production of cytokines, chemokines, and cytotoxic molecules; the mobilization of cells including neutrophils and other leukocytes; the engulfment of pathogens by phagocytosis and their delivery to lysosome for degradation; and the induction of autophagy. Autophagy is a catabolic process that normally maintains cellular homeostasis in a lysosome-dependent manner, but it also functions as a cytoprotective response that intersects with a variety of general stress-response pathways. This review focuses on the intimately linked molecular mechanisms that help govern the autophagic pathway and macrophage innate immune responses.
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Jimenez-Moreno, Natalia, Carla Salomo-Coll, Laura C. Murphy, and Simon Wilkinson. "Signal-Retaining Autophagy Indicator as a Quantitative Imaging Method for ER-Phagy." Cells 12, no. 8 (April 11, 2023): 1134. http://dx.doi.org/10.3390/cells12081134.
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Autophagy is an intracellular lysosomal degradation pathway by which cytoplasmic cargoes are removed to maintain cellular homeostasis. Monitoring autophagy flux is crucial to understand the autophagy process and its biological significance. However, assays to measure autophagy flux are either complex, low throughput or not sensitive enough for reliable quantitative results. Recently, ER-phagy has emerged as a physiologically relevant pathway to maintain ER homeostasis but the process is poorly understood, highlighting the need for tools to monitor ER-phagy flux. In this study, we validate the use of the signal-retaining autophagy indicator (SRAI), a fixable fluorescent probe recently generated and described to detect mitophagy, as a versatile, sensitive and convenient probe for monitoring ER-phagy. This includes the study of either general selective degradation of the endoplasmic reticulum (ER-phagy) or individual forms of ER-phagy involving specific cargo receptors (e.g., FAM134B, FAM134C, TEX264 and CCPG1). Crucially, we present a detailed protocol for the quantification of autophagic flux using automated microscopy and high throughput analysis. Overall, this probe provides a reliable and convenient tool for the measurement of ER-phagy.
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Mohapatra, Sipra, Tapas Chakraborty, Sonoko Shimizu, Kayoko Ohta, Yoshitaka Nagahama, and Kohei Ohta. "Estrogen and estrogen receptors chauffeur the sex-biased autophagic action in liver." Cell Death & Differentiation 27, no. 11 (June 1, 2020): 3117–30. http://dx.doi.org/10.1038/s41418-020-0567-3.
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Santiago-OFarrill, Janice M., Jing Guo, Hailing Yang, Maggie Mao, Zhen Lu, and Robert Bast. "Abstract 2515: DIRAS3 suppresses ovarian cancer cell growth through the inhibition of fibronectin-mediated FAK/AKT signaling." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2515. http://dx.doi.org/10.1158/1538-7445.am2023-2515.
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Abstract Autophagy is a highly conserved cellular process that maintains homeostasis by degrading and recycling long-lived or misfolded proteins and damaged organelles. In addition, autophagy can protect cells from diverse types of cellular stress produced by amino acid starvation and hypoxia, providing energy to retain the function of organelles and cellular signaling pathways. In cancer, autophagy can play dual roles, inhibiting tumor cell growth and viability or sustaining cancer cells in hypoxic, nutrient poor microenvironments. DIRAS3 (ARHI), a maternally imprinted tumor suppressor gene, encodes a 26-kDa GTPase that has 60% homology to Ras and is downregulated in the majority of ovarian cancers. Re-expression of DIRAS3 inhibits growth of ovarian cancer cells, slows their motility and induces autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway. Previously, we have shown that DIRAS3-induced autophagy inhibits ovarian cancer cell growth and promotes autophagic cell death in culture while inducing tumor dormancy in vivo. We have demonstrated that growth factors and extracellular membrane components including fibronectin (FN) in the tumor microenvironment can rescue ovarian cancer cells from DIRAS3-induced autophagic death in cell culture and the use of antibodies against those growth factors or their receptors can eliminate dormant autophagic ovarian cancer cells in ovarian cancer xenografts. In the current study, we explored whether FN, a ubiquitous extracellular matrix (ECM) glycoprotein also plays an important role in DIRAS3-induced tumor dormancy. We hypothesized that FN blocks DIRAS3-induced growth inhibition in ovarian cancer. We investigated the effect of FN on cultured ovarian cancer cells in the presence and absence of DIRAS3. We found that DIRAS3-induced autophagy was inhibited by FN in ovarian cancer cells, judged by decreased conversion of LC3I to LC3II on Western blots and reduced LC3 puncta detected by fluorescence staining. We also found that FN partially rescues ovarian cancer cells from DIRAS3-induced cell death in culture. Mechanistically, FN weakened the inhibitory effect of DIRAS3 on p-FAK and p-AKT, whereas addition of neutralizing antibody against integrin β1 decreased p-FAK and p-AKT. In addition, FN and FN-mediated FAK/AKT signaling is elevated in tumor xenograft tissue when compared to cancer cells in culture. Pharmacologic inhibition of FAK using defactinib, enhanced DIRAS3-induced autophagy, inducing cell death in ovarian cancer cells in the presence of FN. Together, our data demonstrate that factors such as FN, block DIRAS3-induced autophagic cell death, contributing to the survival of ovarian cancer cells. Citation Format: Janice M. Santiago-OFarrill, Jing Guo, Hailing Yang, Maggie Mao, Zhen Lu, Robert Bast. DIRAS3 suppresses ovarian cancer cell growth through the inhibition of fibronectin-mediated FAK/AKT signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2515.
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Kumar, Ravinder, Ankit Shroff, and Taras Y. Nazarko. "Komagataella phaffii Cue5 Piggybacks on Lipid Droplets for Its Vacuolar Degradation during Stationary Phase Lipophagy." Cells 11, no. 2 (January 10, 2022): 215. http://dx.doi.org/10.3390/cells11020215.
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Recently, we developed Komagataella phaffii (formerly Pichia pastoris) as a model for lipophagy, the selective autophagy of lipid droplets (LDs). We found that lipophagy pathways induced by acute nitrogen (N) starvation and in stationary (S) phase have different molecular mechanisms. Moreover, both types of lipophagy are independent of Atg11, the scaffold protein that interacts with most autophagic receptors and, therefore, is essential for most types of selective autophagy in yeast. Since yeast aggrephagy, the selective autophagy of ubiquitinated protein aggregates, is also independent of Atg11 and utilizes the ubiquitin-binding receptor, Cue5, we studied the relationship of K. phaffii Cue5 with differentially induced LDs and lipophagy. While there was no relationship of Cue5 with LDs and lipophagy under N-starvation conditions, Cue5 accumulated on LDs in S-phase and degraded together with LDs via S-phase lipophagy. The accumulation of Cue5 on LDs and its degradation by S-phase lipophagy strongly depended on the ubiquitin-binding CUE domain and Prl1, the positive regulator of lipophagy 1. However, unlike Prl1, which is required for S-phase lipophagy, Cue5 was dispensable for it suggesting that Cue5 is rather a new substrate of this pathway. We propose that a similar mechanism (Prl1-dependent accumulation on LDs) might be employed by Prl1 to recruit another ubiquitin-binding protein that is essential for S-phase lipophagy.
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Sanwald, Julia L., Jochen Dobner, Indra M. Simons, Gereon Poschmann, Kai Stühler, Alina Üffing, Silke Hoffmann, and Dieter Willbold. "Lack of GABARAP-Type Proteins Is Accompanied by Altered Golgi Morphology and Surfaceome Composition." International Journal of Molecular Sciences 22, no. 1 (December 23, 2020): 85. http://dx.doi.org/10.3390/ijms22010085.
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GABARAP (γ-aminobutyric acid type A receptor-associated protein) and its paralogues GABARAPL1 and GABARAPL2 comprise a subfamily of autophagy-related Atg8 proteins. They are studied extensively regarding their roles during autophagy. Originally, however, especially GABARAPL2 was discovered to be involved in intra-Golgi transport and homotypic fusion of post-mitotic Golgi fragments. Recently, a broader function of mammalian Atg8s on membrane trafficking through interaction with various soluble N-ethylmaleimide-sensitive factor-attachment protein receptors (SNAREs) was suggested. By immunostaining and microscopic analysis of the Golgi network, we demonstrate the importance of the presence of individual GABARAP-type proteins on Golgi morphology. Furthermore, triple knockout (TKO) cells lacking the whole GABARAP subfamily showed impaired Golgi-dependent vesicular trafficking as assessed by imaging of fluorescently labelled ceramide. With the Golgi apparatus being central within the secretory pathway, we sought to investigate the role of the GABARAP-type proteins for cell surface protein trafficking. By analysing the surfaceome composition of TKOs, we identified a subset of cell surface proteins with altered plasma membrane localisation. Taken together, we provide novel insights into an underrated aspect of autophagy-independent functions of the GABARAP subfamily and recommend considering the potential impact of GABARAP subfamily proteins on a plethora of processes during experimental analysis of GABARAP-deficient cells not only in the autophagic context.
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Bologna, Cinzia, Roberta Buonincontri, Sara Serra, Tiziana Vaisitti, Valentina Audrito, Davide Brusa, Andrea Pagnani, et al. "SLAMF1/CD150 Activates Autophagy in Chronic Lymphocytic Leukemia Cells, Modulating Chemotaxis and Responses to Therapy." Blood 126, no. 23 (December 3, 2015): 1728. http://dx.doi.org/10.1182/blood.v126.23.1728.1728.
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Abstract Human SLAMF1 (signaling-lymphocytic-activation-molecule-family1, CD150) is a self-ligand adhesion/co-stimulatory molecule wich belongs to a family of 9 receptors. SLAMF1 is also a microbial sensor, as it regulates Gram- bacterial phagosome functions through an ubiquitous cellular autophagic machinery and serves as a receptor for Measles virus. In this work, we investigated expression and function of SLAMF1 in chronic lymphocytic leukemia (CLL) cells. Results indicate that expression of SLAMF1 is lost in a subset of patients with chronic lymphocytic leukemia characterized by an aggressive form of the disease, with shorter time to first treatment (median 2.2 years in SLAMF1- vs 7.6 in SLAMF1+ patients, P=.001) and overall survival (77.5% survival rate at 10 years in SLAMF1- vs 94.7% years in SLAMF1+ patients, P=.036). Consistently, SLAMF1low CLL patients are characterized by clinical or molecular markers of a more aggressive disease. Stable silencing of SLAMF1 in the CLL-like Mec-1 cell line (constitutively SLAMF1+) modulated pathways related to cell migration, cytoskeletal organization and intracellular vesicle formation/recirculation. Decreased expression of CXCR3 and an increased expression of CXCR4, CD38 and CD44 were maintained at the molecular level, likely explaining why SLAMF1- cells show enhanced chemotactic responses to CXCL12. This phenotype was confirmed in primary cells, by comparing a cohorts of SLAMF1high to one of SLAMF1low patients. Gene expression profiling also indicates profound modulation of pathways connected with vesicle formation and recirculation. Consistently, cross-linking of SLAMF1 with an agonisic mAb in primary cells and in the Mec-1 cell line enhanced the generation of autophagic vesicles and their fusion with the lysosomes. Ligation of SLAMF1 with this agonistic monoclonal antibody promoted the autophagic flux, by increasing accumulation of reactive oxygen species (ROS) and inducing phosphorylation of p38, JNK1/2 and bcl-2. The direct consequence was the formation of the autophagy macro-complex containing SLAMF1, the scaffold protein beclin1 and the enzyme Vps34. In agreement with the observation that many drugs used in CLL have autophagy-mediated effects, including fludarabine and the BH3 mimetic ABT-737, SLAMF1-silenced Mec-1 cells or SLAMF1low primary CLL cells were resistant to treatment with both agents. These results indicate that SLAMF1 plays as a critical role in CLL homeostasis. Loss of SLAMF1 expression modulates genetic pathways that regulate chemotaxis and autophagy and that potentially affect drug responses, thus providing a likely explanation for the unfavorable clinical outcome experienced by this patient subset. Restoring SLAMF1 expression in CLL cells would therefore be of therapeutic value for patients with aggressive CLL. Disclosures Gaidano: Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory boards; Celgene: Research Funding.
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Muñoz-Sánchez, Salomé, Michiel van der Vaart, and Annemarie H. Meijer. "Autophagy and Lc3-Associated Phagocytosis in Zebrafish Models of Bacterial Infections." Cells 9, no. 11 (October 29, 2020): 2372. http://dx.doi.org/10.3390/cells9112372.
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Modeling human infectious diseases using the early life stages of zebrafish provides unprecedented opportunities for visualizing and studying the interaction between pathogens and phagocytic cells of the innate immune system. Intracellular pathogens use phagocytes or other host cells, like gut epithelial cells, as a replication niche. The intracellular growth of these pathogens can be counteracted by host defense mechanisms that rely on the autophagy machinery. In recent years, zebrafish embryo infection models have provided in vivo evidence for the significance of the autophagic defenses and these models are now being used to explore autophagy as a therapeutic target. In line with studies in mammalian models, research in zebrafish has shown that selective autophagy mediated by ubiquitin receptors, such as p62, is important for host resistance against several bacterial pathogens, including Shigella flexneri, Mycobacterium marinum, and Staphylococcus aureus. Furthermore, an autophagy related process, Lc3-associated phagocytosis (LAP), proved host beneficial in the case of Salmonella Typhimurium infection but host detrimental in the case of S. aureus infection, where LAP delivers the pathogen to a replication niche. These studies provide valuable information for developing novel therapeutic strategies aimed at directing the autophagy machinery towards bacterial degradation.
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Sheng, Weibei, Qichang Wang, Haotian Qin, Siyang Cao, Yihao Wei, Jian Weng, Fei Yu, and Hui Zeng. "Osteoarthritis: Role of Peroxisome Proliferator-Activated Receptors." International Journal of Molecular Sciences 24, no. 17 (August 24, 2023): 13137. http://dx.doi.org/10.3390/ijms241713137.
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Osteoarthritis (OA) represents the foremost degenerative joint disease observed in a clinical context. The escalating issue of population aging significantly exacerbates the prevalence of OA, thereby imposing an immense annual economic burden on societies worldwide. The current therapeutic landscape falls short in offering reliable pharmaceutical interventions and efficient treatment methodologies to tackle this growing problem. However, the scientific community continues to dedicate significant efforts towards advancing OA treatment research. Contemporary studies have discovered that the progression of OA may be slowed through the strategic influence on peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated receptors within the nuclear hormone receptor family. The three distinctive subtypes—PPARα, PPARβ/δ, and PPARγ—find expression across a broad range of cellular terminals, thus managing a multitude of intracellular metabolic operations. The activation of PPARγ and PPARα has been shown to efficaciously modulate the NF-κB signaling pathway, AP-1, and other oxidative stress-responsive signaling conduits, leading to the inhibition of inflammatory responses. Furthermore, the activation of PPARγ and PPARα may confer protection to chondrocytes by exerting control over its autophagic behavior. In summation, both PPARγ and PPARα have emerged as promising potential targets for the development of effective OA treatments.
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Lakatos, Lőrincz, Szabó, Benkő, Kenéz, Csizmadia, and Juhász. "Sec20 is Required for Autophagic and Endocytic Degradation Independent of Golgi-ER Retrograde Transport." Cells 8, no. 8 (July 24, 2019): 768. http://dx.doi.org/10.3390/cells8080768.
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Endocytosis and autophagy are evolutionarily conserved degradative processes in all eukaryotes. Both pathways converge to the lysosome where cargo is degraded. Improper lysosomal degradation is observed in many human pathologies, so its regulatory mechanisms are important to understand. Sec20/BNIP1 (BCL2/adenovirus E1B 19 kDa protein-interacting protein 1) is a BH3 (Bcl-2 homology 3) domain-containing SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptors) protein that has been suggested to promote Golgi-ER retrograde transport, mitochondrial fission, apoptosis and mitophagy in yeast and vertebrates. Here, we show that loss of Sec20 in Drosophila fat cells causes the accumulation of autophagic vesicles and prevents proper lysosomal acidification and degradation during bulk, starvation-induced autophagy. Furthermore, Sec20 knockdown leads to the enlargement of late endosomes and accumulation of defective endolysosomes in larval Drosophila nephrocytes. Importantly, the loss of Syx18 (Syntaxin 18), one of the known partners of Sec20, led to similar changes in nephrocytes and fat cells. Interestingly. Sec20 appears to function independent of its role in Golgi-ER retrograde transport in regulating lysosomal degradation, as the loss of its other partner SNAREs Use1 (Unconventional SNARE In The ER 1) and Sec22 or tethering factor Zw10 (Zeste white 10), which function together in the Golgi-ER pathway, does not cause defects in autophagy or endocytosis. Thus, our data identify a potential new transport route specific to lysosome biogenesis and function.
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Jeong, Jae-Kyo, and Sang-Youel Park. "Melatonin regulates the autophagic flux via activation of alpha-7 nicotinic acetylcholine receptors." Journal of Pineal Research 59, no. 1 (April 10, 2015): 24–37. http://dx.doi.org/10.1111/jpi.12235.
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Chang, Chi-Lun, Ming-Chih Ho, Po-Huang Lee, Chi-Yen Hsu, Wei-Pang Huang, and Hsinyu Lee. "S1P5 is required for sphingosine 1-phosphate-induced autophagy in human prostate cancer PC-3 cells." American Journal of Physiology-Cell Physiology 297, no. 2 (August 2009): C451—C458. http://dx.doi.org/10.1152/ajpcell.00586.2008.
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Sphingosine 1-phosphate (S1P) is a platelet- and endothelial cell-released lysophospholipid that regulates various cellular functions through activating a specific family of G protein-coupled receptors. Both platelet activation and angiogenesis play important roles in cancer development, implying that cancer cells might encounter a large amount of S1P during these processes. Cancer cells, in the meantime, may experience nutrient deprivation and rely on autophagy for early development. Whether extracellular S1P regulates autophagy remains to be tested. In the present work, we investigated whether autophagy is regulated by S1P in PC-3 cells. Through monitoring the modification patterns of LC3 by Western blotting, we demonstrated that autophagy was induced by exogenously applied S1P in PC-3 cells. This observation was further confirmed by fluorescence microscopy using PC-3 cells stably expressing enhanced green fluorescent protein-LC3. By applying small interfering RNA and dihydro-S1P, S1P5 activation was found to be involved in this process. Besides, mammalian target of rapamycin signaling was inhibited upon S1P treatment. Taken together, our results suggest that, under serum-starved conditions, S1P further upregulates autophagic activity through S1P5-dependent pathways in PC-3 cells.