Journal articles: 'LAMP2a'

1

Cuervo, A. M., and J. F. Dice. "Unique properties of lamp2a compared to other lamp2 isoforms." Journal of Cell Science 113, no. 24 (December 15, 2000): 4441–50. http://dx.doi.org/10.1242/jcs.113.24.4441.

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Lamp2a acts as a receptor in the lysosomal membrane for substrate proteins of chaperone-mediated autophagy. Using antibodies specific for the cytosolic tail of lamp2a and others recognizing all lamp2 isoforms, we found that in rat liver lamp2a represents 25% of lamp2s in the lysosome. We show that lamp2a levels in the lysosomal membrane in rat liver and fibroblasts in culture directly correlate with rates of chaperone-mediated autophagy in a variety of physiological and pathological conditions. The concentration of other lamp2s in the lysosomal membrane show no correlation under the same conditions. Furthermore, substrate proteins bind to lamp2a but not to other lamp2s. Four positively-charged amino acids uniquely present in the cytosolic tail of lamp2a are required for the binding of substrate proteins. Lamp2a also distributes to an unique subpopulation of perinuclear lysosomes in cultured fibroblasts in response to serum withdrawal, and lamp2a, more than other lamp2s, tends to multimerize. These characteristics may be important for lamp2a to act as a receptor for chaperone-mediated autophagy.

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Fukushima, Masaya, Tatsuya Inoue, Takashi Miyai, and Ryo Obata. "Retinal dystrophy associated with Danon disease and pathogenic mechanism through LAMP2-mutated retinal pigment epithelium." European Journal of Ophthalmology 30, no. 3 (March 5, 2019): 570–78. http://dx.doi.org/10.1177/1120672119832183.

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Introduction: Lysosome-associated membrane protein 2 plays an important role in autophagy and lysosomal function and its mutation is responsible for pathogenesis of Danon disease, which can cause retinopathy, though its pathophysiological contribution to retinal dysfunction remains unclear. The purpose of our research is to report the first case of Japanese Danon disease retinopathy and to understand how LAMP2 dysfunction contributes to pathogenesis of retinopathy. Methods: One case underwent ophthalmic examination including slit-lamp exam, fundus imaging, visual field testing, and electroretinogram. In molecular biological study, relative messenger RNA expression levels of three splicing variants of Lamp2 or LAMP2 in wild type mouse retina and retinal pigment epithelium, human retinal pigment epithelium cell line adult retinal pigment epithelium-19 were quantified. LAMP2 was knocked down by small interfering RNA in adult retinal pigment epithelium-19 and its effect to LC3, an autophagy marker, was assessed by Western blotting. Intracellular localization of LAMP2 and LC3 in untreated and LAMP2-knocked-down adult retinal pigment epithelium-19 was analyzed by confocal microscopy. Results: Our case manifested cone dystrophy in both eyes. In mice, expression of Lamp2a and Lamp2b was significantly higher in retinal pigment epithelium than that in neural retina. Expression of Lamp2a and Lamp2b were significantly higher than that of Lamp2c in mouse retinal pigment epithelium. Adult retinal pigment epithelium-19 cells showed similar LAMP2 expression pattern to mouse retinal pigment epithelium. LAMP2 knockdown in adult retinal pigment epithelium-19 reduced LC3-II amount and the number and size of autophagosome. Discussion: We report a Japanese case of Danon disease retinopathy, and our study implies that LAMP2 plays an important role in autophagosome formation in retinal pigment epithelium.

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Manso, Ana Maria, Sherin I. Hashem, Bradley C. Nelson, Emily Gault, Angel Soto-Hermida, Elizza Villarruel, Michela Brambatti, et al. "Systemic AAV9.LAMP2B injection reverses metabolic and physiologic multiorgan dysfunction in a murine model of Danon disease." Science Translational Medicine 12, no. 535 (March 18, 2020): eaax1744. http://dx.doi.org/10.1126/scitranslmed.aax1744.

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Danon disease (DD) is a rare X-linked autophagic vacuolar myopathy associated with multiorgan dysfunction, including the heart, skeletal muscle, and liver. There are no specific treatments, and most male patients die from advanced heart failure during the second or third decade of life. DD is caused by mutations in the lysosomal-associated membrane protein 2 (LAMP2) gene, a key mediator of autophagy. LAMP2 has three isoforms: LAMP2A, LAMP2B, and LAMP2C. LAMP2B is the predominant isoform expressed in cardiomyocytes. This study evaluates the efficacy of human LAMP2B gene transfer using a recombinant adeno-associated virus 9 carrying human LAMP2B (AAV9.LAMP2B) in a Lamp2 knockout (KO) mouse, a DD model. AAV9.LAMP2B was intravenously injected into 2- and 6-month-old Lamp2 KO male mice to assess efficacy in adolescent and adult phenotypes. Lamp2 KO mice receiving AAV9.LAMP2B demonstrated dose-dependent restoration of human LAMP2B protein in the heart, liver, and skeletal muscle tissue. Impaired autophagic flux, evidenced by increased LC3-II, was abrogated by LAMP2B gene transfer in all tissues in both cohorts. Cardiac function was also improved, and transaminases were reduced in AAV9.LAMP2B-treated KO mice, indicating favorable effects on the heart and liver. Survival was also higher in the older cohort receiving high vector doses. No anti-LAMP2 antibodies were detected in mice that received AAV9.LAMP2B. In summary, LAMP2B gene transfer improves metabolic and physiologic function in a DD murine model, suggesting that a similar therapeutic approach may be effective for treating patients with this highly morbid disease.

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Auzmendi-Iriarte, Jaione, Maddalen Otaegi-Ugartemendia, Estefania Carrasco-Garcia, Mikel Azkargorta, Antonio Diaz, Ander Saenz-Antoñanzas, Joaquin Andrés Andermatten, et al. "Chaperone-Mediated Autophagy Controls Proteomic and Transcriptomic Pathways to Maintain Glioma Stem Cell Activity." Cancer Research 82, no. 7 (February 7, 2022): 1283–97. http://dx.doi.org/10.1158/0008-5472.can-21-2161.

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Abstract Chaperone-mediated autophagy (CMA) is a homeostatic process essential for the lysosomal degradation of a selected subset of the proteome. CMA activity directly depends on the levels of LAMP2A, a critical receptor for CMA substrate proteins at the lysosomal membrane. In glioblastoma (GBM), the most common and aggressive brain cancer in adulthood, high levels of LAMP2A in the tumor and tumor-associated pericytes have been linked to temozolomide resistance and tumor progression. However, the role of LAMP2A, and hence CMA, in any cancer stem cell type or in glioblastoma stem cells (GSC) remains unknown. In this work, we show that LAMP2A expression is enriched in patient-derived GSCs, and its depletion diminishes GSC-mediated tumorigenic activities. Conversely, overexpression of LAMP2A facilitates the acquisition of GSC properties. Proteomic and transcriptomic analysis of LAMP2A-depleted GSCs revealed reduced extracellular matrix interaction effectors in both analyses. Moreover, pathways related to mitochondrial metabolism and the immune system were differentially deregulated at the proteome level. Furthermore, clinical samples of GBM tissue presented overexpression of LAMP2, which correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA in directly regulating GSCs activity via multiple pathways at the proteome and transcriptome levels. Significance: A receptor of chaperone-mediated autophagy regulates glioblastoma stem cells and may serve as a potential biomarker for advanced tumor grade and poor survival in this disease.

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Lescat, Laury, Vincent Véron, Brigitte Mourot, Sandrine Péron, Nathalie Chenais, Karine Dias, Natàlia Riera-Heredia, et al. "Chaperone-Mediated Autophagy in the Light of Evolution: Insight from Fish." Molecular Biology and Evolution 37, no. 10 (May 21, 2020): 2887–99. http://dx.doi.org/10.1093/molbev/msaa127.

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Abstract Chaperone-mediated autophagy (CMA) is a major pathway of lysosomal proteolysis recognized as a key player of the control of numerous cellular functions, and whose defects have been associated with several human pathologies. To date, this cellular function is presumed to be restricted to mammals and birds, due to the absence of an identifiable lysosome-associated membrane protein 2A (LAMP2A), a limiting and essential protein for CMA, in nontetrapod species. However, the recent identification of expressed sequences displaying high homology with mammalian LAMP2A in several fish species challenges that view and suggests that CMA likely appeared earlier during evolution than initially thought. In the present study, we provide a comprehensive picture of the evolutionary history of the LAMP2 gene in vertebrates and demonstrate that LAMP2 indeed appeared at the root of the vertebrate lineage. Using a fibroblast cell line from medaka fish (Oryzias latipes), we further show that the splice variant lamp2a controls, upon long-term starvation, the lysosomal accumulation of a fluorescent reporter commonly used to track CMA in mammalian cells. Finally, to address the physiological role of Lamp2a in fish, we generated knockout medaka for that specific splice variant, and found that these deficient fish exhibit severe alterations in carbohydrate and fat metabolisms, in consistency with existing data in mice deficient for CMA in liver. Altogether, our data provide the first evidence for a CMA-like pathway in fish and bring new perspectives on the use of complementary genetic models, such as zebrafish or medaka, for studying CMA in an evolutionary perspective.

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Tang, Wanjun, Karrie Mei Yee Kiang, and Gilberto Ka Kit Leung. "Abstract A011: Enhancing chaperone-mediated autophagy to impede glioblastoma growth." Molecular Cancer Therapeutics 23, no. 6_Supplement (June 10, 2024): A011. http://dx.doi.org/10.1158/1538-8514.synthleth24-a011.

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Abstract Chaperone-mediated autophagy (CMA) is a selective form of autophagy that targets proteins with the KFERQ-like motif for lysosomal degradation. This process involves the binding of substrate proteins to the chaperone HSC70 and their subsequent transport to the receptor LAMP2A on the lysosome membrane for degradation. Previous studies have shown a significant increase in the expression level of LAMP2A and the CMA activity in glioblastoma (GBM). However, the comprehensive role of CMA in GBM pathogenesis remains unclear. In this study, we observed a progressive elevation in LAMP2A expression with increasing GBM cell confluence. Notably, inhibition of CMA through LAMP2A knockdown markedly promoted GBM growth in orthotopic mouse models, accompanied by upregulation of positive cell cycle regulators. Conversely, overexpression of LAMP2A delayed GBM cell growth and increased sub-G1 cell percentages. Treatment with CMA activators induced cell death in GBM cells while preserving normal astrocyte viability at equivalent concentrations. Our results suggest that the upregulated expression of LAMP2A in GBM cells may be influenced by the tumor microenvironment rather than being a primary driver of GBM aggressiveness. Furthermore, activating CMA could serve as a potential therapeutic strategy to inhibit GBM growth while safeguarding normal cell viability. Citation Format: Wanjun Tang, Karrie Mei Yee Kiang, Gilberto Ka Kit Leung. Enhancing chaperone-mediated autophagy to impede glioblastoma growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A011.

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Losmanová, Tereza, Félice A. Janser, Magali Humbert, Igor Tokarchuk, Anna M. Schläfli, Christina Neppl, Ralph A. Schmid, Mario P. Tschan, Rupert Langer, and Sabina Berezowska. "Chaperone-Mediated Autophagy Markers LAMP2A and HSC70 Are Independent Adverse Prognostic Markers in Primary Resected Squamous Cell Carcinomas of the Lung." Oxidative Medicine and Cellular Longevity 2020 (September 22, 2020): 1–12. http://dx.doi.org/10.1155/2020/8506572.

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LAMP2A and HSC70 are crucial players in chaperone-mediated autophagy (CMA), a targeted, lysosome-dependent protein degradation pathway. Elevated LAMP2A levels, indicative of increased CMA activity, are observed in several malignancies, and CMA downregulation may be exploited therapeutically. We evaluated the impact of LAMP2A and HSC70 in pulmonary squamous cell carcinomas (pSQCC). Antibodies were validated by knockdown and overexpression experiments using three different cell lines. Expression levels in tissue were analyzed by immunohistochemistry in a cohort of 336 consecutive pSQCC using tissue microarrays. There was no significant correlation between the two markers among each other and no association with pathological parameters (TNM categories, grading). However, both high LAMP2A and HSC70 expression were associated with worse outcome, including overall survival (OS; p=0.012 and p=0.001) and disease free survival (DFS; p=0.049 and p=0.036). In multivariate analysis, both markers and a combination of them were independent adverse prognostic factors for OS (LAMP2Ahigh: HR=2.059; p<0.001; HSC70high: HR=1.987; p<0.001; LAMP2Ahigh/HSC70high: HR=1.529; p<0.001) and DFS (LAMP2Ahigh: HR=1.709; p=0.004; HSC70high: HR=1.484; p=0.027; LAMP2Ahigh/HSC70high: HR=1.342, p<0.001). The negative prognostic impact of high LAMP2A and HSC70 and their variable expression in pSQCC may justify the use of these proteins as potential biomarkers for future CMA-inhibiting therapies.

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Magnaeva, Alina S., Tat'yana I. Baranich, Dmitry N. Voronkov, Anna A. Gofman, Tat'yana S. Gulevskaya, Valeriya V. Glinkina, and Vladimir S. Sukhorukov. "IMMUNOHISTOCHEMICAL EVALUATION OF CHAPERONE-INDUCED AUTOPHAGY IN VARIOUS PARTS OF THE HUMAN BRAIN DURING AGING." Morphological newsletter 31, no. 1 (January 30, 2023): 27–33. http://dx.doi.org/10.20340/mv-mn.2023.31(1).724.

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Supporting of the functional pool of neurons during age-related brain involution is closely related to chaperone-mediated autophagy, the main function of which is to provide cellular proteostasis and utilize neurotoxic proteins. Impairment of this type of autophagy underlies the pathogenesis of many age-associated neurodegenerative diseases. In this aspect, it seems relevant to study the relationship between key markers of chaperone-mediated autophagy and their relative contribution to aging and neurodegeneration in order to determine pharmaceutical targets. The aim of the study was to determine the levels of expression of markers of chaperone-mediated autophagy - heat shock protein 70 (HSP70) and lysosome-associated membrane protein type 2A (LAMP2) in neurons of various areas of the human brain during aging. The study was performed on autopsy material of patients whose causes of death were not associated with neurological diseases. Preparations of the cortex of the precentral gyrus, striatum and hippocampus were studied in the group of cases of young age (35-45 years, n=5) and senile age (>75 years, n=10). Immunohistochemical staining was performed using primary antibodies to HSP70 and LAMP2. Optical density was assessed in the perikaryon of 150 large neurons in layer V of the cortex of the precentral gyrus, striatum, and pyramidal layer of the hippocampus. The results of the study demonstrated an increase in the expression of both HSP70 and LAMP2A in brain preparations from cases of senile age. The higher values of the optical density of HSP70 compared to LAMP2A in brain preparations from senile cases were probably due to dissociation between the stage of substrate binding and the stage of its translocation. It can be assumed that the binding of nonfunctioning proteins to HSP70 and cochaperones occurs faster than their movement into the lumen of lysosomes via LAMP2A. The results obtained suggest that the increasing of levels of markers of chaperone-mediated autophagy may be of a compensatory-adaptive nature and ensure the survival of neurons under conditions of chronic stress during physiological aging.

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Kim, Jin-Wook, Feriel Mahiddine, and Geon Kim. "Leptin Modulates the Metastasis of Canine Inflammatory Mammary Adenocarcinoma Cells through Downregulation of Lysosomal Protective Protein Cathepsin A (CTSA)." International Journal of Molecular Sciences 21, no. 23 (November 25, 2020): 8963. http://dx.doi.org/10.3390/ijms21238963.

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Canine malignant mammary gland tumors present with a poor prognosis due to metastasis to other organs, such as lung and lymph node metastases. Unlike in human studies where obesity has been shown to increase the risk of breast cancer, this has not been well studied in veterinary science. In our preliminary study, we discovered that leptin downregulated cathepsin A, which is responsible for lysosomal-associated membrane protein 2a (LAMP2a) degradation. LAMP2a is a rate-limiting factor in chaperone-mediated autophagy and is highly active in malignant cancers. Therefore, in this study, alterations in metastatic capacity through cathepsin A by leptin, which are secreted at high levels in the blood of obese patients, were investigated. We used a canine inflammatory mammary gland adenocarcinoma (CHMp) cell line cultured with RPMI-1640 and 10% fetal bovine serum. The samples were then subjected to real-time polymerase chain reaction, Western blot, immunocytochemistry, and lysosome isolation to investigate and visualize the metastasis and chaperone-mediated autophagy-related proteins. Results showed that leptin downregulated cathepsin A expression at both transcript and protein levels, whereas LAMP2a, the rate-limiting factor of chaperone-mediated autophagy, was upregulated by inhibition of LAMP2a degradation. Furthermore, leptin promoted LAMP2a multimerization through the lysosomal mTORC2 (mTOR complex 2)/PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1)/AKT1 (Serine/threonine-protein kinase 1) pathway. These findings suggest that targeting leptin receptors can alleviate mammary gland cancer cell metastasis in dogs.

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Sahu, Ranjit, Satwinder Singh, and Anne Davidson. "Statins induce microautophagy in RAW 264.7 cell line. (APP3P.107)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 111.8. http://dx.doi.org/10.4049/jimmunol.192.supp.111.8.

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Abstract Autophagy is process by which cells recycle cellular components to overcome starvation. This process is constitutive in antigen presenting cells such as dendritic cells and macrophages. Among the various autophagy pathways, microautophagy (Mi) has a unique significance as it is implicated in the biogenesis of exosomes which are relevant to the design of therapeutics. Statins have been shown to up regulate macroautophagy and alleviate the effect of LPS apart from inhibiting cholesterol synthesis. However their role in microautophagy has not been reported. In the present study we investigated the effect of statins on microautophagy using the RAW264.7 cell line as a model system. Treatment with statins resulted in an up regulation of the genes for MA as well as Mi as determined by qPCR. Further studies showed that the levels of proteins TSG101 and VPS4 were increased during statin treatment. Pretreatment with statins led to a lowering of LAMP2A levels and decreased LAMP2A on the late endosomes, mimicking a LAMP2A knock down. Pretreatment with statins not only lowered the transcription of iNOS and TNF-alpha genes but also prevented the effect of LPS by decreasing initial levels of LAMP2A and increasing levels of TSG101. We propose that Mi can be a surrogate for Chaperone mediated autophagy (CMA) under conditions where the components of CMA are rendered non-functional due to disruption in normal cellular metabolism.

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Chen, Jinyun, Yujie Yang, Wade A. Russu, and William K. Chan. "The Aryl Hydrocarbon Receptor Undergoes Chaperone-Mediated Autophagy in Triple-Negative Breast Cancer Cells." International Journal of Molecular Sciences 22, no. 4 (February 6, 2021): 1654. http://dx.doi.org/10.3390/ijms22041654.

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The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule expressed in many cell types, including triple-negative and non-triple-negative breast cancer cells. It affects breast cancer growth and crosstalk with estrogen receptor signaling. Normally, this receptor is degraded shortly after ligand activation via the 26S proteasome. Here, we report that AHR undergoes chaperone-mediated autophagy in MDA-MB-468 triple-negative breast cancer cells. This lysosomal degradation of AHR exhibits the following characteristics: (1) it is triggered by 6 amino-nicotinamide, starvation, and piperazinylpyrimidine compound Q18; (2) it is not observed in non-triple-negative breast cancer cells (MCF-7, T47D, and MDA-MB-361); (3) it can be inhibited by progesterone receptor B but not estrogen receptor alpha; (4) it can be reversed by chloroquine but not MG132; (5) it requires LAMP2A; and (6) it involves AHR-HSC70 and AHR-LAMP2A interactions. The NEKFF sequence localized at amino acid 558 of human AHR appears to be a KFERQ-like motif of chaperone-mediated autophagy, responsible for the LAMP2A-mediated AHR protein degradation.

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Chen, Rui, Peng Li, Yan Fu, Zongyao Wu, Lijun Xu, Junhua Wang, Sha Chen, et al. "Chaperone-mediated autophagy promotes breast cancer angiogenesis via regulation of aerobic glycolysis." PLOS ONE 18, no. 3 (March 13, 2023): e0281577. http://dx.doi.org/10.1371/journal.pone.0281577.

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Evidence shows that chaperone-mediated autophagy (CMA) is involved in cancer cell pathogenesis and progression. However, the potential role of CMA in breast cancer angiogenesis remains unknown. We first manipulated CMA activity by knockdown and overexpressing of lysosome-associated membrane protein type 2A (LAMP2A) in MDA-MB-231, MDA-MB-436, T47D and MCF7 cells. We found that the tube formation, migration and proliferation abilities of human umbilical vein endothelial cells (HUVECs) were inhibited after cocultured with tumor-conditioned medium from breast cancer cells of LAMP2A knockdown. While the above changes were promoted after cocultured with tumor-conditioned medium from breast cancer cells of LAMP2A overexpression. Moreover, we found that CMA could promote VEGFA expression in breast cancer cells and in xenograft model through upregulating lactate production. Finally, we found that lactate regulation in breast cancer cells is hexokinase 2 (HK2) dependent, and knockdown of HK2 can significantly reduce the ability of CMA-mediated tube formation capacity of HUVECs. Collectively, these results indicate that CMA could promote breast cancer angiogenesis via regulation of HK2-dependent aerobic glycolysis, which may serve as an attractive target for breast cancer therapies.

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Meneses-Salas, Elsa, Ana García-Melero, Patricia Blanco-Muñoz, Jaimy Jose, Marie-Sophie Brenner, Albert Lu, Francesc Tebar, Thomas Grewal, Carles Rentero, and Carlos Enrich. "Selective Degradation Permits a Feedback Loop Controlling Annexin A6 and Cholesterol Levels in Endolysosomes of NPC1 Mutant Cells." Cells 9, no. 5 (May 7, 2020): 1152. http://dx.doi.org/10.3390/cells9051152.

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We recently identified elevated annexin A6 (AnxA6) protein levels in Niemann–Pick-type C1 (NPC1) mutant cells. In these cells, AnxA6 depletion rescued the cholesterol accumulation associated with NPC1 deficiency. Here, we demonstrate that elevated AnxA6 protein levels in NPC1 mutants or upon pharmacological NPC1 inhibition, using U18666A, were not due to upregulated AnxA6 mRNA expression, but caused by defects in AnxA6 protein degradation. Two KFERQ-motifs are believed to target AnxA6 to lysosomes for chaperone-mediated autophagy (CMA), and we hypothesized that the cholesterol accumulation in endolysosomes (LE/Lys) triggered by the NPC1 inhibition could interfere with the CMA pathway. Therefore, AnxA6 protein amounts and cholesterol levels in the LE/Lys (LE-Chol) compartment were analyzed in NPC1 mutant cells ectopically expressing lysosome-associated membrane protein 2A (Lamp2A), which is well known to induce the CMA pathway. Strikingly, AnxA6 protein amounts were strongly decreased and coincided with significantly reduced LE-Chol levels in NPC1 mutant cells upon Lamp2A overexpression. Therefore, these findings suggest Lamp2A-mediated restoration of CMA in NPC1 mutant cells to lower LE-Chol levels with concomitant lysosomal AnxA6 degradation. Collectively, we propose CMA to permit a feedback loop between AnxA6 and cholesterol levels in LE/Lys, encompassing a novel mechanism for regulating cholesterol homeostasis in NPC1 disease.

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Losmanova, Tereza, Philipp Zens, Amina Scherz, Ralph A. Schmid, Mario P. Tschan, and Sabina Berezowska. "Chaperone-Mediated Autophagy Markers LAMP2A and HSPA8 in Advanced Non-Small Cell Lung Cancer after Neoadjuvant Therapy." Cells 10, no. 10 (October 13, 2021): 2731. http://dx.doi.org/10.3390/cells10102731.

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In recent years autophagy has attracted the attention of researchers from many medical fields, including cancer research, and certain anti-macroautophagy drugs in combination with cytotoxic or targeted therapies have entered clinical trials. In the present study, we focused on a less explored subtype of autophagy, i.e., chaperone-mediated autophagy (CMA), with the key proteins LAMP2A and HSPA8 (HSC70), and their immunohistochemical evaluation with previously extensively validated antibodies. We were interested in whether the marker expression is influenced by the antecedent therapy, and its correlation with survival on a cohort of patients with non-small cell lung cancer (NSCLC) after neoadjuvant therapy and matched primary resected tumors. In concordance with our previous study, we did not find any intratumoral heterogeneity, nor correlation between the two parameters, nor correlation between the markers and any included pathological parameters. Surprisingly, the expression of both markers was also independent to tumor response or administered neoadjuvant treatment. In the survival analysis, the results were only significant for LAMP2A, where higher levels were associated with longer 5-year overall survival and disease-free survival for the mixed group of adenocarcinomas and squamous cell carcinomas (p < 0.0001 and p = 0.0019 respectively) as well as the squamous cell carcinoma subgroup (p = 0.0001 and p = 0.0001 respectively). LAMP2A was also an independent prognostic marker in univariate and multivariate analysis.

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Cuervo, A. M., and J. F. Dice. "Regulation of Lamp2a Levels in the Lysosomal Membrane." Traffic 1, no. 7 (July 2000): 570–83. http://dx.doi.org/10.1034/j.1600-0854.2000.010707.x.

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Choi, Seung Ho, and KyoungJoo Cho. "LAMP2A-mediated autophagy involved in Huntington’s disease progression." Biochemical and Biophysical Research Communications 534 (January 2021): 561–67. http://dx.doi.org/10.1016/j.bbrc.2020.11.042.

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Xilouri, Maria, Oeystein Roed Brekk, Deniz Kirik, and Leonidas Stefanis. "LAMP2A as a therapeutic target in Parkinson disease." Autophagy 9, no. 12 (December 5, 2013): 2166–68. http://dx.doi.org/10.4161/auto.26451.

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Ikami, Yuta, Kazue Terasawa, Kensaku Sakamoto, Kazumasa Ohtake, Hiroyuki Harada, Tetsuro Watabe, Shigeyuki Yokoyama, and Miki Hara-Yokoyama. "The two-domain architecture of LAMP2A regulates its interaction with Hsc70." Experimental Cell Research 411, no. 1 (February 2022): 112986. http://dx.doi.org/10.1016/j.yexcr.2021.112986.

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Jing, Huang, Wu Maodong, Sun Zhenjie, and Li Aimin. "Protective Effect of Aloperine on Dopamine Neurons of Parkinson's Disease by Activating Autophagy." Journal of Biomaterials and Tissue Engineering 10, no. 5 (May 1, 2020): 602–8. http://dx.doi.org/10.1166/jbt.2020.2367.

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Objection: To investigate whether Aloperine protects dopamine neurons in Parkinson's disease (PD) by activating autophagy and discuss its specific mechanism. Methods: C57BL/6 male mice were performed treated with MPTP (30 mg/kg) once daily for 7 d continuously to establish PD models. Dividing mice into Normal, Model, Alo and Alo+3-methyladenine (3-MA) groups. Aloperine (80 mg/kg) and Aloperine (80 mg/kg)+ 3-MA (2 mg/kg) were added into the mice of Alo and Alo+ 3-MA groups at the time of MPTP injection once daily. In the normal control group, sterile saline was injected into the abdomen simultaneously (30 ml/kg). Measuring apoptosis cell number by TUNEL assay, evaluating TH positive cell number, LAMP2A, α-Syn and LC3 including LC3-I and LC3-II proteins expression by IHC assay. Results: The apoptosis cell number of Model group was significantly increased (P < 0 05); Alo treatment, apoptosis cell number was significantly depressed (P < 0 05); while, the 3-MA supplement, the apoptosis cell number was significantly up-regulation (P < 0 05). Meanwhile, with Alo supplement, the relative protein including LAMP2A, -Syn, LC3-I and LC3-II proteins expressions were improved. Conclusion: Alo improved Parkinson's disease via regulation autophagy in vivo study.

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Maglica, Mirko, Nela Kelam, Ilija Perutina, Anita Racetin, Azer Rizikalo, Natalija Filipović, Ivana Kuzmić Prusac, Josip Mišković, and Katarina Vukojević. "Immunoexpression Pattern of Autophagy-Related Proteins in Human Congenital Anomalies of the Kidney and Urinary Tract." International Journal of Molecular Sciences 25, no. 13 (June 21, 2024): 6829. http://dx.doi.org/10.3390/ijms25136829.

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The purpose of this study was to evaluate the spatiotemporal immunoexpression pattern of microtubule-associated protein 1 light chain 3 beta (LC3B), glucose-regulated protein 78 (GRP78), heat shock protein 70 (HSP70), and lysosomal-associated membrane protein 2A (LAMP2A) in normal human fetal kidney development (CTRL) and kidneys affected with congenital anomalies of the kidney and urinary tract (CAKUT). Human fetal kidneys (control, horseshoe, dysplastic, duplex, and hypoplastic) from the 18th to the 38th developmental week underwent epifluorescence microscopy analysis after being stained with antibodies. Immunoreactivity was quantified in various kidney structures, and expression dynamics were examined using linear and nonlinear regression modeling. The punctate expression of LC3B was observed mainly in tubules and glomerular cells, with dysplastic kidneys displaying distinct staining patterns. In the control group’s glomeruli, LAMP2A showed a sporadic, punctate signal; in contrast to other phenotypes, duplex kidneys showed significantly stronger expression in convoluted tubules. GRP78 had a weaker expression in CAKUT kidneys, especially hypoplastic ones, while normal kidneys exhibited punctate staining of convoluted tubules and glomeruli. HSP70 staining varied among phenotypes, with dysplastic and hypoplastic kidneys exhibiting stronger staining compared to controls. Expression dynamics varied among observed autophagy markers and phenotypes, indicating their potential roles in normal and dysfunctional kidney development.

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Maglica, Mirko, Nela Kelam, Ejazul Haque, Ilija Perutina, Anita Racetin, Natalija Filipović, Yu Katsuyama, and Katarina Vukojević. "Immunoexpression Pattern of Autophagy Markers in Developing and Postnatal Kidneys of Dab1−/−(yotari) Mice." Biomolecules 13, no. 3 (February 21, 2023): 402. http://dx.doi.org/10.3390/biom13030402.

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The purpose of this study was to compare the immunofluorescence patterns of autophagic markers: Light chain 3 beta (LC3B), Glucose regulating protein 78 (GRP78), Heat shock cognate 71 (HSC70) and Lysosomal-associated membrane protein 2A (LAMP2A) in the developing and postnatal kidneys of Dab1−/− (yotari) mice to those of wild-type samples. Embryos were obtained on gestation days 13.5 and 15.5 (E13.5 and E15.5), and adult animals were sacrificed at postnatal days 4, 11 and 14 (P4, P11, and P14). After fixation and dehydration, paraffin-embedded kidney tissues were sectioned and incubated with specific antibodies. Using an immunofluorescence microscope, sections were analyzed. For statistical analysis, a two-way ANOVA test and a Tukey’s multiple comparison test were performed with a probability level of p < 0.05. A significant increase in GRP78 and LAMP2A expression was observed in the renal vesicles and convoluted tubules of yotari in embryonic stages. In postnatal kidneys, all observed proteins showed higher signal intensities in proximal and distal convoluted tubules of yotari, while a higher percentage of LC3B-positive cells was also observed in glomeruli. Our findings suggest that all of the examined autophagic markers play an important role in normal kidney development, as well as the potential importance of these proteins in renal pathology, where they primarily serve a protective function and thus may be used as diagnostic and therapeutic targets.

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Rahman, Farhana D., Jennifer L. Johnson, and Sergio D. Catz. "Regulation of the chaperone‐mediated autophagy receptor LAMP2A by DYNC1LI2 in cystinosis." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.07326.

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Wang, Ruibo, Yantong Liu, Li Liu, Mei Chen, Xiuxuan Wang, Jingyun Yang, Yanqiu Gong, Bi-Sen Ding, Yuquan Wei, and Xiawei Wei. "Tumor cells induce LAMP2a expression in tumor-associated macrophage for cancer progression." EBioMedicine 40 (February 2019): 118–34. http://dx.doi.org/10.1016/j.ebiom.2019.01.045.

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Pajares, Marta, Ana I. Rojo, Esperanza Arias, Antonio Diaz-Carretero, Ana Maria Cuervo, and Antonio Cuadrado. "Transcription factor NRF2 modulates chaperone mediated autophagy through the regulation of LAMP2A." Free Radical Biology and Medicine 120 (May 2018): S28. http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.098.

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Sukhorukov, Vladimir, Alina Magnaeva, Tatiana Baranich, Anna Gofman, Dmitry Voronkov, Tatiana Gulevskaya, Valeria Glinkina, and Sergey Illarioshkin. "Brain Neurons during Physiological Aging: Morphological Features, Autophagic and Mitochondrial Contribution." International Journal of Molecular Sciences 23, no. 18 (September 14, 2022): 10695. http://dx.doi.org/10.3390/ijms231810695.

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Accumulating data suggest that the brain undergoes various changes during aging. Among them are loss of both white and gray matter, neurons and synapses degeneration, as well as oxidative, inflammatory, and biochemical changes. The above-mentioned age-related features are closely related to autophagy and mitochondria. Therefore, we aimed to reveal the most peculiar morphological features of brain nervous tissue and to characterize the expression of autophagy and mitochondrial immunohistochemical biomarkers in neurons of different human brain zones during aging. Counting the number of neurons as well as Microtubule-associated proteins 1A/1B light chain 3B (LC3B), Heat shock protein 70 (HSP70), Lysosome-associated membrane protein type 2A (LAMP2A), Alpha subunit of ATP synthase (ATP5A), and Parkinson disease protein 7 (DJ1) immunohistochemical staining were performed on FFPE samples of human prefrontal cortex, corpus striatum, and hippocampus obtained from autopsy. Statistical analysis revealed a loss of neurons in the studied elderly group in comparison to the young group. When the expression of macroautophagy (LC3B), chaperon-mediated autophagy (HSP70, LAMP2A), and mitochondrial respiratory chain complex V (ATP5A) markers for the young and elderly groups were compared, the latter was found to have a significantly higher rate of optical density, whilst there was no significance in DJ1 expression. These findings, while preliminary, suggest that both autophagy and mitochondria are involved in neuronal maintenance during aging and could indicate their potential role in adaptive mechanisms that occur in aging.

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Pajares, Marta, Ana I. Rojo, Esperanza Arias, Antonio Díaz-Carretero, Ana María Cuervo, and Antonio Cuadrado. "Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A." Autophagy 14, no. 8 (July 26, 2018): 1310–22. http://dx.doi.org/10.1080/15548627.2018.1474992.

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Saha, Tapas. "LAMP2A overexpression in breast tumors promotes cancer cell survival via chaperone-mediated autophagy." Autophagy 8, no. 11 (November 9, 2012): 1643–56. http://dx.doi.org/10.4161/auto.21654.

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Ding, Zhen-Bin, Xiu-Tao Fu, Ying-Hong Shi, Jian Zhou, Yuan-Fei Peng, Wei-Ren Liu, Guo-Ming Shi, et al. "Lamp2a is required for tumor growth and promotes tumor recurrence of hepatocellular carcinoma." International Journal of Oncology 49, no. 6 (November 3, 2016): 2367–76. http://dx.doi.org/10.3892/ijo.2016.3754.

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Das, Suvarthi, Ratanesh Kumar Seth, Ashutosh Kumar, Maria B. Kadiiska, Gregory Michelotti, Anna Mae Diehl, and Saurabh Chatterjee. "Purinergic receptor X7 is a key modulator of metabolic oxidative stress-mediated autophagy and inflammation in experimental nonalcoholic steatohepatitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 305, no. 12 (December 15, 2013): G950—G963. http://dx.doi.org/10.1152/ajpgi.00235.2013.

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Recent studies indicate that metabolic oxidative stress, autophagy, and inflammation are hallmarks of nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanisms that link these important events in NASH remain unclear. In this study, we investigated the mechanistic role of purinergic receptor X7 (P2X7) in modulating autophagy and resultant inflammation in NASH in response to metabolic oxidative stress. The study uses two rodent models of NASH. In one of them, a CYP2E1 substrate bromodichloromethane is used to induce metabolic oxidative stress and NASH. Methyl choline-deficient diet feeding is used for the other NASH model. CYP2E1 and P2X7 receptor gene-deleted mice are used to establish their roles in regulating metabolic oxidative stress and autophagy. Autophagy gene expression, protein levels, confocal microscopy based-immunolocalization of lysosome-associated membrane protein (LAMP)2A and histopathological analysis were performed. CYP2E1-dependent metabolic oxidative stress induced increases in P2X7 receptor expression and chaperone-mediated autophagy markers LAMP2A and heat shock cognate 70 but caused depletion of light chain 3 isoform B (LC3B) protein levels. P2X7 receptor gene deletion significantly decreased LAMP2A and inflammatory indicators while significantly increasing LC3B protein levels compared with wild-type mice treated with bromodichloromethane. P2X7 receptor-deleted mice were also protected from NASH pathology as evidenced by decreased inflammation and fibrosis. Our studies establish that P2X7 receptor is a key regulator of autophagy induced by metabolic oxidative stress in NASH, thereby modulating hepatic inflammation. Furthermore, our findings presented here form a basis for P2X7 receptor as a potential therapeutic target in the treatment for NASH.

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Li, Guo-Li, Ying-Qian Han, Bing-Qian Su, Hai-Shen Yu, Shuang Zhang, Guo-Yu Yang, Jiang Wang, Fang Liu, Sheng-Li Ming, and Bei-Bei Chu. "Porcine reproductive and respiratory syndrome virus 2 hijacks CMA-mediated lipolysis through upregulation of small GTPase RAB18." PLOS Pathogens 20, no. 4 (April 12, 2024): e1012123. http://dx.doi.org/10.1371/journal.ppat.1012123.

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RAB GTPases (RABs) control intracellular membrane trafficking with high precision. In the present study, we carried out a short hairpin RNA (shRNA) screen focused on a library of 62 RABs during infection with porcine reproductive and respiratory syndrome virus 2 (PRRSV-2), a member of the family Arteriviridae. We found that 13 RABs negatively affect the yield of PRRSV-2 progeny virus, whereas 29 RABs have a positive impact on the yield of PRRSV-2 progeny virus. Further analysis revealed that PRRSV-2 infection transcriptionally regulated RAB18 through RIG-I/MAVS-mediated canonical NF-κB activation. Disrupting RAB18 expression led to the accumulation of lipid droplets (LDs), impaired LDs catabolism, and flawed viral replication and assembly. We also discovered that PRRSV-2 co-opts chaperone-mediated autophagy (CMA) for lipolysis via RAB18, as indicated by the enhanced associations between RAB18 and perlipin 2 (PLIN2), CMA-specific lysosomal associated membrane protein 2A (LAMP2A), and heat shock protein family A (Hsp70) member 8 (HSPA8/HSC70) during PRRSV-2 infection. Knockdown of HSPA8 and LAMP2A impacted on the yield of PRRSV-2 progeny virus, implying that the virus utilizes RAB18 to promote CMA-mediated lipolysis. Importantly, we determined that the C-terminal domain (CTD) of HSPA8 could bind to the switch II domain of RAB18, and the CTD of PLIN2 was capable of associating with HSPA8, suggesting that HSPA8 facilitates the interaction between RAB18 and PLIN2 in the CMA process. In summary, our findings elucidate how PRRSV-2 hijacks CMA-mediated lipid metabolism through innate immune activation to enhance the yield of progeny virus, offering novel insights for the development of anti-PRRSV-2 treatments.

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Garg, A. D., A. M. Dudek, and P. Agostinis. "Calreticulin surface exposure is abrogated in cells lacking, chaperone-mediated autophagy-essential gene, LAMP2A." Cell Death & Disease 4, no. 10 (October 2013): e826-e826. http://dx.doi.org/10.1038/cddis.2013.372.

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Sato, Masahiro, Tomoko Ohta, Takahiro Seki, Ayumu Konno, Hirokazu Hirai, Yuki Kurauchi, and Hiroshi Katsuki. "Motor dysfunction is triggered by miRNA-mediated knockdown of LAMP2A in mouse cerebellar neurons." Proceedings for Annual Meeting of The Japanese Pharmacological Society 93 (2020): 2—P—187. http://dx.doi.org/10.1254/jpssuppl.93.0_2-p-187.

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La Rosa, Francesca, Chiara Paola Zoia, Chiara Bazzini, Alessandra Bolognini, Marina Saresella, Elisa Conti, Carlo Ferrarese, et al. "Modulation of MAPK- and PI3/AKT-Dependent Autophagy Signaling by Stavudine (D4T) in PBMC of Alzheimer’s Disease Patients." Cells 11, no. 14 (July 12, 2022): 2180. http://dx.doi.org/10.3390/cells11142180.

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Background: Aβ42 deposition plays a pivotal role in AD pathogenesis by inducing the activation of microglial cells and neuroinflammation. This process is antagonized by microglia-mediated clearance of Aβ plaques. Activation of the NLRP3 inflammasome is involved in neuroinflammation and in the impairments of Aβ-plaque clearance. On the other hand, stavudine (D4T) downregulates the NLRP3 inflammasome and stimulates autophagy-mediated Aβ-clearing in a THP-1-derived macrophages. Methods: We explored the effect of D4T on Aβ autophagy in PBMC from AD patients that were primed with LPS and stimulated with Aβ oligomers in the absence/presence of D4T. We analyzed the NLRP3 activity by measuring NLRP3-ASC complex formation by AMNIS FlowSight and pro-inflammatory cytokine (IL-1β, IL-18 and Caspase-1) production by ELISA. The phosphorylation status of p38, ERK, AKT, p70, and the protein expression of CREB, LAMP2A, beclin-1, Caspase-3 and Bcl2 were analyzed by Western blot. Results: Data showed that D4T: (1) downregulates NLRP3 inflammasome activation and the production of down-stream pro-inflammatory cytokines in PBMC; (2) stimulates the phosphorylation of AKT, ERK and p70 as well as LAMP2A, beclin-1 and Bcl2 expression and reduces Caspase-3 expression, suggesting an effect of this compound on autophagy; (3) increases phospho-CREB, which is a downstream target of p-ERK and p-AKT, inducing anti-inflammatory cytokine production and resulting in a possible decrease of Aβ-mediated cytotoxicity; and (4) reduces the phosphorylation of p38, a protein involved in the production of pro-inflammatory cytokines and tau hyperphosphorylation. Conclusions: D4T reduces the activation of the NLRP3 inflammasome, and it might stimulate autophagy as well as the molecular mechanism that modulates Aβ cytotoxicity, and D4T might reduce inflammation in the cells of AD patients. It could be very interesting to check the possible beneficial effects of D4T in the clinical scenario.

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Nikesitch, Nicholas, Patricia Rebeiro, Lye Lin Ho, Srinivasa Pothula, Xin Maggie Wang, Tiffany Khong, Hazel Quek, et al. "The Role of Chaperone-Mediated Autophagy in Bortezomib Resistant Multiple Myeloma." Cells 10, no. 12 (December 8, 2021): 3464. http://dx.doi.org/10.3390/cells10123464.

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Background: Multiple myeloma (MM) remains incurable despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Even with the improved survival of MM patients treated with novel agents, including bortezomib (Bz), the therapeutic options in relapsed/refractory MM remain limited. The majority of MM patients eventually develop resistance to Bz, although the mechanisms of the resistance are poorly understood. Methods: Lysosomal associated membrane protein 2A (LAMP2A) mRNA and protein expression levels were assessed in ex vivo patient samples and a Bz-resistant MM cell line model by in real-rime PCR, western blotting and immunohistochemistry. In vitro modelling of chaperone-mediated autophagy (CMA) activity in response to ER stress were assessed by western blotting and confocal microscopy. The effects of CMA inhibition on MM cell viability and Bz sensitivity in MM cells were assessed by Annexin V/7AAD apoptosis assays using flow cytometry. Results: In this study, there is evidence that CMA, a chaperone-mediated protein degradation pathway, is upregulated in Bz-resistant MM and the inhibition of CMA sensitises resistant cells to Bz. The protein levels of LAMP2A, the rate-limiting factor of the CMA pathway, are significantly increased in MM patients resistant to Bz and within our Bz-resistant cell line model. Bz-resistant cell lines also possessed higher basal CMA activity than the Bz-sensitive parent cell line. In MM cell lines, CMA activity was upregulated in response to ER stress induced by Bz. The inhibition of CMA sensitises Bz-resistant cells to Bz and the combination of CMA inhibition and Bz in vitro had a more cytotoxic effect on myeloma cells than Bz alone. Conclusion: In summary, the upregulation of CMA is a potential mechanism of resistance to Bz and a novel target to overcome Bz-resistant MM.

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Jin, Ying, Yamu Pan, Shuang Zheng, Yao Liu, Jie Xu, Yazhi Peng, Zemei Zhang, et al. "Inactivation of EGLN3 hydroxylase facilitates Erk3 degradation via autophagy and impedes lung cancer growth." Oncogene 41, no. 12 (February 5, 2022): 1752–66. http://dx.doi.org/10.1038/s41388-022-02203-2.

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AbstractEGLN3 is critically important for growth of various cancers including lung cancer. However, virtually nothing is known about the role and mechanism for EGLN3 hydroxylase activity in cancers. EGLN3 catalyzes the hydroxylation of extracellular signal-regulated kinase 3 (Erk3), a potent driver of cancers. The role and mechanism for EGLN3-induced stabilization of Erk3 remain to be defined. Here, we show that Erk3 interacts with heat shock cognate protein of 70 kDa (HSC70) and lysosome-associated membrane protein type 2 A (LAMP2A), two core components of chaperone-mediated autophagy (CMA). As a consequence, Erk3 is degraded by the CMA-lysosome pathway. EGLN3-catalyzed hydroxylation antagonizes CMA-dependent destruction of Erk3. Mechanistically, hydroxylation blunts the interaction of Erk3 with LAMP2A, thereby blocking lysosomal decay of Erk3. EGLN3 inactivation inhibits macrophage migration, efferocytosis, and M2 polarization. Studies using EGLN3 catalytically inactive knock-in mice indicate that inactivation of EGLN3 hydroxylase in host cells ameliorates LLC cancer growth through reprogramming the tumor microenvironment (TME). Adoptive transfer of macrophages with inactivated EGLN3 restrains tumor growth by mounting anti-tumor immunity and restricting angiogenesis. Administration of EGLN3 hydroxylase pharmacologic inhibitor to mice bearing LLC carcinoma impedes cancer growth by targeting the TME. LLC cells harboring inactivated EGLN3 exhibit reduced tumor burden via mitigating immunosuppressive milieu and inducing cancer senescence. This study provides novel insights into the role of CMA in regulating Erk3 stability and the mechanism behind EGLN3-enhanced stability of Erk3. This work demonstrates that inactivation of EGLN3 in malignant and stromal cells suppresses tumor by orchestrating reciprocal interplays between cancer cells and the TME. This work sheds new light on the role and mechanism for EGLN3 catalytic activity in regulating cancer growth. Manipulating EGLN3 activity holds promise for cancer treatment.

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Zhou, Hong, Xin Xie, Ying Chen, Yi Lin, Zhaogen Cai, Li Ding, Yijie Wu, Yongde Peng, Shanshan Tang, and Huanbai Xu. "Chaperone-mediated Autophagy Governs Progression of Papillary Thyroid Carcinoma via PPARγ-SDF1/CXCR4 Signaling." Journal of Clinical Endocrinology & Metabolism 105, no. 10 (June 18, 2020): 3308–23. http://dx.doi.org/10.1210/clinem/dgaa366.

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Abstract Context Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. Chaperone-mediated autophagy (CMA), 1 type of autophagy, is thought to promote or suppress cancer development in different cancer types. However, the effect of CMA on PTC development and the underlying mechanisms remain unknown. Objective To determine whether CMA plays implied critical roles in the development of PTC. Design We investigated the association between CMA and PTC development in PTC tissues and normal thyroid tissues by detecting the key protein of CMA, lysosome-associated membrane protein type 2A (LAMP2A), using quantitative polymerase chain reaction (PCR) and immunohistochemistry, which were further validated in the TGCA dataset. The effect of CMA on PTC development was studied by cell proliferation, migration, and apoptosis assays. The underlying mechanisms of peroxisome proliferator-activated receptor γ (PPARγ)-stromal cell-derived factor 1 (SDF1)/ C-X-C motif chemokine receptor 4 (CXCR4) signaling were clarified by western blotting, quantitative PCR, and rescue experiments. Knockdown and tamoxifen were used to analyze the effect of estrogen receptor (ER) α on CMA. Results Our study confirmed that CMA, indicated by LAMP2A expression, was significantly increased in PTC tumor tissues and cell lines, and was associated with tumor size and lymph node metastasis of patients. Higher CMA in PTC promoted tumor cell proliferation and migration, thereby promoting tumor growth and metastasis. These effects of CMA on PTC were exerted by decreasing PPARγ protein expression to enhance SDF1 and CXCR4 expression. Furthermore, CMA was found positively regulated by ERα signaling in PTC. Conclusion Our investigation identified CMA regulated by ERα promoting PTC tumor progression that enhanced tumor cell proliferation and migration by targeting PPARγ-SDF1/CXCR4 signaling, representing a potential target for treatment of PTC.

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Fan, Y., T. Hou, T. Liu, J. Zeng, and L. Li. "PrLZ stabilizes LAMP2A to promote chaperone-mediated autophagy and tumor growth of prostate cancer cells." European Urology Supplements 18, no. 1 (March 2019): e345. http://dx.doi.org/10.1016/s1569-9056(19)30257-x.

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Catarino, Steve, Paulo Pereira, and Henrique Girão. "Molecular control of chaperone-mediated autophagy." Essays in Biochemistry 61, no. 6 (December 12, 2017): 663–74. http://dx.doi.org/10.1042/ebc20170057.

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Chaperone-mediated autophagy (CMA) is a selective form of autophagy in which cytosolic proteins bearing a pentapeptide motif biochemically related to the KFERQ sequence, are recognized by the heat shock protein family A member 8 (HSPA8) chaperone, delivered to the lysomal membrane, and directly translocated across the lysosomal membrane by a protein complex containing lysosomal associated membrane protein 2a (Lamp2a). Since its discovery over two decades ago, the importance of this pathway in cell proteostasis has been made increasingly apparent. Deregulation of this pathway has been implicated in a variety of diseases and conditions, including lysosomal storage diseases, cancer, neurodegeneration and even aging. Here, we describe the main molecular features of the pathway, its regulation, cross-talk with other degradation pathways and importance in disease.

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Martínez-González, Javier, Ángel Fernández-Carbonell, Antolin Cantó, Roberto Gimeno-Hernández, Inmaculada Almansa, Francisco Bosch-Morell, María Miranda, and Teresa Olivar. "Sequences of Alterations in Inflammation and Autophagy Processes in Rd1 Mice." Biomolecules 13, no. 9 (August 22, 2023): 1277. http://dx.doi.org/10.3390/biom13091277.

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(1) Background: the aim of this work was to study microglia and autophagy alterations in a one retinitis pigmentosa (RP) model at different stages of the disease (when rods are dying and later, when there are almost no rods, and cones are the cells that die. (2) Methods: rd1 mice were used and retinas obtained at postnatal days (PN) 11, 17, 28, 35, and 42. Iba1 (ionized calcium-binding adapter molecule 1) was the protein selected to study microglial changes. The macroautophagy markers Beclin-1, Atg5, Atg7, microtubule-associated protein light chain 3 (LC3), and lysosomal-associated membrane protein 2 (LAMP2) (involved in chaperone-mediated autophagy (CMA)) were determined. (3) Results: the expression of Iba1 was increased in rd1 retinas compared to the control group at PN17 (after the period of maximum rod death), PN28 (at the beginning of the period of cone death), and PN42. The number of activated (ameboid) microglial cells increased in the early ages of the retinal degeneration and the deactivated forms (branched cells) in more advanced ages. The macroautophagy markers Atg5 at PN11, Atg7 and LC3II at PN17, and Atg7 again at PN28 were decreased in rd1 retinas. At PN35 and PN42, the results reveal alterations in LAMP2A, a marker of CMA in the retina of rd1 mice. (4) Conclusions: we can conclude that during the early phases of retinal degeneration in the rd1 mouse, there is an alteration in microglia and a decrease in the macroautophagy cycle. Subsequently, the CMA is decreased and later on appears activated as a compensatory mechanism.

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Ikami, Yuta, Kazue Terasawa, Tetsuro Watabe, Shigeyuki Yokoyama, and Miki Hara-Yokoyama. "The two-domain architecture of LAMP2A within the lysosomal lumen regulates its interaction with HSPA8/Hsc70." Autophagy Reports 1, no. 1 (May 1, 2022): 205–9. http://dx.doi.org/10.1080/27694127.2022.2069968.

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Lee, Wonseok, Hyun Young Kim, You-Jin Choi, Seung-Hwan Jung, Yoon Ah Nam, Yunfan Zhang, Sung Ho Yun, Tong-Shin Chang, and Byung-Hoon Lee. "SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation." Theranostics 12, no. 5 (2022): 2351–69. http://dx.doi.org/10.7150/thno.70692.

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Lorenzo, I., U. Nogueira-Recalde, N. Oreiro, J. A. Pinto Tasende, M. Lotz, F. J. Blanco, and B. Carames. "POS0375 CHAPERONE-MEDIATED AUTOPHAGY IS A HALLMARK OF JOINT DISEASE IN OSTEOARTHRITIC PATIENTS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 418.1–418. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2639.

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Background:In Osteoarthritis (OA), defects in macroautophagy (autophagy) are evident and precede joint damage. Indeed, pharmacological activation of autophagy protects against joint damage.Objectives:Therefore, identifying hallmarks associated with specific autophagy subtypes could shed light to fundamental mechanisms of joint disease.Methods:A comparative analysis of 35 autophagy genes was performed from blood from the Prospective OA Cohort of A Coruña (PROCOAC). Non-OA subjects (Age:61,44±1,16 years; BMI:25,25±0,52; Females, n=18) and Knee OA subjects (Age:65,50±1,05 years; BMI:29,55±0,67; Females, n=18, OA grade III-IV) were profiled using an autophagy gene expression array by SYBR green qPCR. Confirmatory studies were performed in blood from Non-OA subjects (Age:60,13±1,12 years; BMI:24,85±0,59; Females; n=30) and Knee-OA subjects (Age:68,4±1,11 years; BMI:29,65±0,55; Females; n=30, OA grade III-IV) by Taqman qPCR. The candidate gene was evaluated in human knee joint tissues (cartilage, meniscus, ligaments, synovium) with different KL grades (Age: KL0=28,3±4,50; KL2=77±6,08; KL4=62,3±3,05, n=3) and in both spontaneous aging (2, 6, 12, 18, and 30 months old, n=3) and surgically-induced OA (10 weeks after surgery, n=4) in mice by IHC. The functional consequences were studied in T/C28a2 and primary human OA chondrocytes. Autophagy, FOXO, Chaperone-mediated autophagy (CMA), inflammation, and cellular senescence were analyzing by gene and protein expression. Moreover, oxidative stress and cell death were evaluated by FACS. The contribution of CMA to chondrocyte homeostasis was evaluated by studying the capacity of CMA to restore proteostasis upon autophagy deficiency by siATG5.Results:15 autophagy-related genes were significantly downregulated in blood from knee OA patients compared to non-OA patients. No significant upregulation was found for any studied gene, although a trend towards upregulation was found in genes involved in the mTOR pathway. Four key autophagy-related genes, including ATG16L2, ATG12, ATG4B and MAP1LC3B were found downregulated in knee OA patients. Interestingly, HSP90AA1 and HSPA8, CMA markers involved in stress response and protein folding, were downregulated. Confirmatory studies showed a significant downregulation of MAP1LC3B and HSP90AA1 in blood from knee OA patients. Remarkably, HSP90A was found reduced in femoral cartilage (medial and lateral), meniscus and ACL. Moreover, this reduction was higher in medial cartilage compared to lateral cartilage and meniscus, while in synovial membrane, HSP90A expression was found increased. This expression signature was dependent on OA grade severity. In addition, we observed a decrease of HSP90A with aging and OA in mice. The functional consequences of HSP90AA1 gene silencing are related to an increase in NFκB, MMP13, and p16 expression. Interestingly, LAMP2A, a key CMA mediator, HSPA8, MAP1LC3B and FoxO1 expression were upregulated in chondrocytes with HSP90AA1 deficiency, which might indicate an early response to maintain homeostasis. On the other hand, LAMP2A protein is decreased upon HSP90AA1 deficiency, while LC3II and p62 were increased, indicating a failure in the autophagy flux that leads to impaired lysosomal degradation.Moreover, p21, p16 and prbS6 were increased upon HSP90AA1 deficiency, besides increasing mitochondrial ROS production and apoptosis. ATG5 silencing blocks autophagy by reducing LC3II and increasing prbs6, p62, p16 and p21. Interestingly, LAMP2A and HSP90A were found increased, indicating a possible compensative activation of CMA in response to autophagy defects. These results support that HSP90A has an important role in chondrocyte homeostasis by participating in the cross-talk between CMA and autophagy.Conclusion:Taking together, we identified HSP90A, a CMA regulator, as critical in chondrocyte homeostasis. These disease mechanisms are relevant in OA and constitute hallmarks potentially useful to prevent OA progression.References:[1]Caramés B, et al. Arthritis Rheum. 2010, 2015;[2]Caramés B, et al. Ann Rheum Dis. 2012.Disclosure of Interests:None declared

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Rizikalo, Azer, Mirko Maglica, Nela Kelam, Ilija Perutina, Marin Ogorevc, Anita Racetin, Natalija Filipović, et al. "Unraveling the Impact of Dab1 Gene Silencing on the Expression of Autophagy Markers in Lung Development." Life 14, no. 3 (February 28, 2024): 316. http://dx.doi.org/10.3390/life14030316.

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The purpose of this study was to evaluate the effects of Dab1 gene silencing on the immunoexpression of light chain 3 beta (Lc3b), glucose regulating protein 78 (Grp78), heat shock cognate 71 (Hsc70), mammalian target of rapamycin (mTOR) and lysosomal-associated membrane protein 2A (Lamp2a) in the lung tissue of developing yotari (Dab1−/−) and wild-type (wt) mice. The lung epithelium and mesenchyme of the embryos at gestational days E13.5 and E15.5 were examined using immunofluorescence and semi-quantitative methods. In the pulmonary mesenchyme and epithelium, Grp78 and Lc3b of moderate fluorescence reactivity was demonstrated in wt mice for both evaluated time points, while yotari mice exhibited only epithelial reactivity for the same markers. Mild punctate expression of Hsc70 was observed for both genotypes. A significant difference was present when analyzing mTOR expression, where wt mice showed strong perinuclear staining in the epithelium. According to our data, Dab1 gene silencing may result in autophagy abnormalities, which could then cause respiratory system pathologies via defective lung cell degradation by lysosome-dependent cell elimination.

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Issa, Abdul-Raouf, Jun Sun, Céline Petitgas, Ana Mesquita, Amina Dulac, Marion Robin, Bertrand Mollereau, Andreas Jenny, Baya Chérif-Zahar, and Serge Birman. "The lysosomal membrane protein LAMP2A promotes autophagic flux and prevents SNCA-induced Parkinson disease-like symptoms in the Drosophila brain." Autophagy 14, no. 11 (August 10, 2018): 1898–910. http://dx.doi.org/10.1080/15548627.2018.1491489.

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Zhang, Jinzhong, Jennifer L. Johnson, Jing He, Gennaro Napolitano, Mahalakshmi Ramadass, Celine Rocca, William B. Kiosses, et al. "Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A." Journal of Biological Chemistry 292, no. 25 (May 2, 2017): 10328–46. http://dx.doi.org/10.1074/jbc.m116.764076.

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Lo Dico, Alessia, Cristina Martelli, Cecilia Diceglie, and Luisa Ottobrini. "The Multifaceted Role of CMA in Glioma: Enemy or Ally?" International Journal of Molecular Sciences 22, no. 4 (February 23, 2021): 2217. http://dx.doi.org/10.3390/ijms22042217.

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Chaperone-mediated autophagy (CMA) is a catabolic pathway fundamental for cell homeostasis, by which specific damaged or non-essential proteins are degraded. CMA activity has three main levels of regulation. The first regulatory level is based on the targetability of specific proteins possessing a KFERQ-like domain, which can be recognized by specific chaperones and delivered to the lysosomes. Target protein unfolding and translocation into the lysosomal lumen constitutes the second level of CMA regulation and is based on the modulation of Lamp2A multimerization. Finally, the activity of some accessory proteins represents the third regulatory level of CMA activity. CMA’s role in oncology has not been fully clarified covering both pro-survival and pro-death roles in different contexts. Taking all this into account, it is possible to comprehend the actual complexity of both CMA regulation and the cellular consequences of its activity allowing it to be elected as a modulatory and not only catabolic machinery. In this review, the role covered by CMA in oncology is discussed with a focus on its relevance in glioma. Molecular correlates of CMA importance in glioma responsiveness to treatment are described to identify new early efficacy biomarkers and new therapeutic targets to overcome resistance.

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Gao, Huiling, Hehong Sun, Nan Yan, Pu Zhao, He Xu, Wei Zheng, Xiaoyu Zhang, Tao Wang, Chuang Guo, and Manli Zhong. "ATP13A2 Declines Zinc-Induced Accumulation of α-Synuclein in a Parkinson’s Disease Model." International Journal of Molecular Sciences 23, no. 14 (July 21, 2022): 8035. http://dx.doi.org/10.3390/ijms23148035.

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Parkinson’s disease (PD) is characterized by the presence of Lewy bodies caused by α-synuclein. The imbalance of zinc homeostasis is a major cause of PD, promoting α-synuclein accumulation. ATP13A2, a transporter found in acidic vesicles, plays an important role in Zn2+ homeostasis and is highly expressed in Lewy bodies in PD-surviving neurons. ATP13A2 is involved in the transport of zinc ions in lysosomes and exosomes and inhibits the aggregation of α-synuclein. However, the potential mechanism underlying the regulation of zinc homeostasis and α-synuclein accumulation by ATP13A2 remains unexplored. We used α-synuclein-GFP transgenic mice and HEK293 α-synuclein-DsRed cell line as models. The spatial exploration behavior of mice was significantly reduced, and phosphorylation levels of α-synuclein increased upon high Zn2+ treatment. High Zn2+ also inhibited the autophagy pathway by reducing LAMP2a levels and changing the expression of LC3 and P62, by reducing mitochondrial membrane potential and increasing the expression of cytochrom C, and by activating the ERK/P38 apoptosis signaling pathway, ultimately leading to increased caspase 3 levels. These protein changes were reversed after ATP13A2 overexpression, whereas ATP13A2 knockout exacerbated α-synuclein phosphorylation levels. These results suggest that ATP13A2 may have a protective effect on Zn2+-induced abnormal aggregation of α-synuclein, lysosomal dysfunction, and apoptosis.

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Sutkowska-Skolimowska, Joanna, Justyna Brańska-Januszewska, Jakub W. Strawa, Halina Ostrowska, Malwina Botor, Katarzyna Gawron, and Anna Galicka. "Rosemary Extract-Induced Autophagy and Decrease in Accumulation of Collagen Type I in Osteogenesis Imperfecta Skin Fibroblasts." International Journal of Molecular Sciences 23, no. 18 (September 7, 2022): 10341. http://dx.doi.org/10.3390/ijms231810341.

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Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disease mainly caused by structural mutations in type I collagen. Mutant collagen accumulates intracellularly, causing cellular stress that has recently been shown to be phenotype-related. Therefore, the aim of the study was to search for potential drugs reducing collagen accumulation and improving OI fibroblast homeostasis. We found that rosemary extract (RE), which is of great interest to researchers due to its high therapeutic potential, at concentrations of 50 and 100 µg/mL significantly reduced the level of accumulated collagen in the fibroblasts of four patients with severe and lethal OI. The decrease in collagen accumulation was associated with RE-induced autophagy as was evidenced by an increase in the LC3-II/LC3-I ratio, a decrease in p62, and co-localization of type I collagen with LC3-II and LAMP2A by confocal microscopy. The unfolded protein response, activated in three of the four tested cells, and the level of pro-apoptotic markers (Bax, CHOP and cleaved caspase 3) were attenuated by RE. In addition, the role of RE-modulated proteasome in the degradation of unfolded procollagen chains was investigated. This study provides new insight into the beneficial effects of RE that may have some implications in OI therapy targeting cellular stress.

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Ueda, Erika, Tomoko Ohta, Ayumu Konno, Hirokazu Hirai, Yuki Kurauchi, Hiroshi Katsuki, and Takahiro Seki. "D-Cysteine Activates Chaperone-Mediated Autophagy in Cerebellar Purkinje Cells via the Generation of Hydrogen Sulfide and Nrf2 Activation." Cells 11, no. 7 (April 5, 2022): 1230. http://dx.doi.org/10.3390/cells11071230.

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Chaperone-mediated autophagy (CMA) is a pathway in the autophagy-lysosome protein degradation system. CMA impairment has been implicated to play a role in spinocerebellar ataxia (SCA) pathogenesis. D-cysteine is metabolized by D-amino acid oxidase (DAO), leading to hydrogen sulfide generation in the cerebellum. Although D-cysteine alleviates the disease phenotypes in SCA-model mice, it remains unknown how hydrogen sulfide derived from D-cysteine exerts this effect. In the present study, we investigated the effects of D-cysteine and hydrogen sulfide on CMA activity using a CMA activity marker that we have established. D-cysteine activated CMA in Purkinje cells (PCs) of primary cerebellar cultures where DAO was expressed, while it failed to activate CMA in DAO-deficient AD293 cells. In contrast, Na2S, a hydrogen sulfide donor, activated CMA in both PCs and AD293 cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to be activated by hydrogen sulfide and regulate CMA activity. An Nrf2 inhibitor, ML385, prevented CMA activation triggered by D-cysteine and Na2S. Additionally, long-term treatment with D-cysteine increased the amounts of Nrf2 and LAMP2A, a CMA-related protein, in the mouse cerebellum. These findings suggest that hydrogen sulfide derived from D-cysteine enhances CMA activity via Nrf2 activation.

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Espinosa, Rodrigo, Karla Gutiérrez, Javiera Rios, Fernando Ormeño, Liliana Yantén, Pablo Galaz-Davison, César A. Ramírez-Sarmiento, et al. "Palmitic and Stearic Acids Inhibit Chaperone-Mediated Autophagy (CMA) in POMC-like Neurons In Vitro." Cells 11, no. 6 (March 8, 2022): 920. http://dx.doi.org/10.3390/cells11060920.

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The intake of food with high levels of saturated fatty acids (SatFAs) is associated with the development of obesity and insulin resistance. SatFAs, such as palmitic (PA) and stearic (SA) acids, have been shown to accumulate in the hypothalamus, causing several pathological consequences. Autophagy is a lysosomal-degrading pathway that can be divided into macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Previous studies showed that PA impairs macroautophagy function and insulin response in hypothalamic proopiomelanocortin (POMC) neurons. Here, we show in vitro that the exposure of POMC neurons to PA or SA also inhibits CMA, possibly by decreasing the total and lysosomal LAMP2A protein levels. Proteomics of lysosomes from PA- and SA-treated cells showed that the inhibition of CMA could impact vesicle formation and trafficking, mitochondrial components, and insulin response, among others. Finally, we show that CMA activity is important for regulating the insulin response in POMC hypothalamic neurons. These in vitro results demonstrate that CMA is inhibited by PA and SA in POMC-like neurons, giving an overview of the CMA-dependent cellular pathways that could be affected by such inhibition and opening a door for in vivo studies of CMA in the context of the hypothalamus and obesity.

Journal articles on the topic 'LAMP2a'

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