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1
Amick, Joseph, Arun Kumar Tharkeshwar, Catherine Amaya, e Shawn M. Ferguson. "WDR41 supports lysosomal response to changes in amino acid availability". Molecular Biology of the Cell 29, n. 18 (settembre 2018): 2213–27. http://dx.doi.org/10.1091/mbc.e17-12-0703.
Abstract (sommario):
C9orf72 mutations are a major cause of amyotrophic lateral sclerosis and frontotemporal dementia. The C9orf72 protein undergoes regulated recruitment to lysosomes and has been broadly implicated in control of lysosome homeostasis. However, although evidence strongly supports an important function for C9orf72 at lysosomes, little is known about the lysosome recruitment mechanism. In this study, we identify an essential role for WDR41, a prominent C9orf72 interacting protein, in C9orf72 lysosome recruitment. Analysis of human WDR41 knockout cells revealed that WDR41 is required for localization of the protein complex containing C9orf72 and SMCR8 to lysosomes. Such lysosome localization increases in response to amino acid starvation but is not dependent on either mTORC1 inhibition or autophagy induction. Furthermore, WDR41 itself exhibits a parallel pattern of regulated association with lysosomes. This WDR41-dependent recruitment of C9orf72 to lysosomes is critical for the ability of lysosomes to support mTORC1 signaling as constitutive targeting of C9orf72 to lysosomes relieves the requirement for WDR41 in mTORC1 activation. Collectively, this study reveals an essential role for WDR41 in supporting the regulated binding of C9orf72 to lysosomes and solidifies the requirement for a larger C9orf72 containing protein complex in coordinating lysosomal responses to changes in amino acid availability.
2
Talaia, Gabriel, Joseph Amick e Shawn M. Ferguson. "Receptor-like role for PQLC2 amino acid transporter in the lysosomal sensing of cationic amino acids". Proceedings of the National Academy of Sciences 118, n. 8 (17 febbraio 2021): e2014941118. http://dx.doi.org/10.1073/pnas.2014941118.
Abstract (sommario):
PQLC2, a lysosomal cationic amino acid transporter, also serves as a sensor that responds to scarcity of its substrates by recruiting a protein complex composed of C9orf72, SMCR8, and WDR41 to the surface of lysosomes. This protein complex controls multiple aspects of lysosome function. Although it is known that this response to changes in cationic amino acid availability depends on an interaction between PQLC2 and WDR41, the underlying mechanism for the regulated interaction is not known. In this study, we present evidence that the WDR41–PQLC2 interaction is mediated by a short peptide motif in a flexible loop that extends from the WDR41 β-propeller and inserts into a cavity presented by the inward-facing conformation of PQLC2. The data support a transceptor model wherein conformational changes in PQLC2 related to substrate transport regulate the availability of the WDR41-binding site on PQLC2 and mediate recruitment of the WDR41-SMCR8-C9orf72 complex to the surface of lysosomes.
3
Tang, Dan, Jingwen Sheng, Liangting Xu, Xiechao Zhan, Jiaming Liu, Hui Jiang, Xiaoling Shu et al. "Cryo-EM structure of C9ORF72–SMCR8–WDR41 reveals the role as a GAP for Rab8a and Rab11a". Proceedings of the National Academy of Sciences 117, n. 18 (17 aprile 2020): 9876–83. http://dx.doi.org/10.1073/pnas.2002110117.
Abstract (sommario):
A massive intronic hexanucleotide repeat (GGGGCC) expansion in C9ORF72 is a genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, C9ORF72, together with SMCR8 and WDR41, has been shown to regulate autophagy and function as Rab GEF. However, the precise function of C9ORF72 remains unclear. Here, we report the cryogenic electron microscopy (cryo-EM) structure of the human C9ORF72–SMCR8–WDR41 complex at a resolution of 3.2 Å. The structure reveals the dimeric assembly of a heterotrimer of C9ORF72–SMCR8–WDR41. Notably, the C-terminal tail of C9ORF72 and the DENN domain of SMCR8 play critical roles in the dimerization of the two protomers of the C9ORF72–SMCR8–WDR41 complex. In the protomer, C9ORF72 and WDR41 are joined by SMCR8 without direct interaction. WDR41 binds to the DENN domain of SMCR8 by the C-terminal helix. Interestingly, the prominent structural feature of C9ORF72–SMCR8 resembles that of the FLNC–FNIP2 complex, the GTPase activating protein (GAP) of RagC/D. Structural comparison and sequence alignment revealed that Arg147 of SMCR8 is conserved and corresponds to the arginine finger of FLCN, and biochemical analysis indicated that the Arg147 of SMCR8 is critical to the stimulatory effect of the C9ORF72–SMCR8 complex on Rab8a and Rab11a. Our study not only illustrates the basis of C9ORF72–SMCR8–WDR41 complex assembly but also reveals the GAP activity of the C9ORF72–SMCR8 complex.
4
SHARMA, NISHA, REVANASIDDU D, SUSHIL KUMAR, BEENA SINHA, RAGINI KUMARI, I. D. GUPTA e ARCHANA VERMA. "Influence of WDR41 and ANKRD31 gene polymorphism on udder and teat type traits and mastitis in Karan Fries cows". Indian Journal of Animal Sciences 92, n. 2 (10 marzo 2022): 215–21. http://dx.doi.org/10.56093/ijans.v92i2.122096.
Abstract (sommario):
In the present study, the effect of genetic polymorphism of WD-repeat containing protein 41 (WDR41) and Ankyrin repeat domain containing protein 31 (ANKRD31) gene on 17 traits related to udder and teat type and mastitis in 123 Karan Fries cows was studied. Restriction Fragment Length Polymorphism (RFLP) was used to identify the SNP (410 bp and 475 bp) in PCR amplified product of intron 4 and exon 10 in WDR41 gene. Both of them were polymorphic with Guanine to Adenine transition, and three genotypes namely AA, AG and GG were observed. In ANKRD31 gene, RFLP was used to identify the SNP in 513 bp PCR amplified product of intron 24 and two SNPs were found. We report for the first time that intron 4 and exon 10 of WDR41 gene is significantly associated with udder depth (UD), udder balance (UB), central ligament (CL), teat circumference (TC), SFF and tear diameter (TD), rear udder width (RUW), and mastitis. SNP rs110012582 in intron 24 of ANKRD31 gene is associated significantly with UD, distance between left and right teat (DLR), SFF, and SNP rs473512406 with udder length (UL), udder width (UW), udder circumference (UC), fore teat length (FTL), rear teat length (RTL), distance between fore and rear teat (DFR), DLR and mastitis. This information can augment future studies to determine the role of WDR41 and ANKRD31 genes as a candidate gene marker with desired udder and teat conformation and mastitis. Thus, it is essential to work for better udder health and prevent the incidence of mastitis in the herd.
5
McAlpine, William, Lei Sun, Kuan-wen Wang, Aijie Liu, Ruchi Jain, Miguel San Miguel, Jianhui Wang et al. "Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function". Proceedings of the National Academy of Sciences 115, n. 49 (15 novembre 2018): E11523—E11531. http://dx.doi.org/10.1073/pnas.1814753115.
Abstract (sommario):
The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of-function mutations of Smcr8 or C9orf72 in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of C9ORF72. However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in Smcr8−/− mice were rescued by triple knockout of the endosomal Toll-like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from Smcr8−/− mice produced excessive inflammatory cytokines in response to endocytosed TLR3, TLR7, or TLR9 ligands administered in the growth medium and in response to TLR2 or TLR4 ligands internalized by phagocytosis. These defects likely stem from prolonged TLR signaling caused by accumulation of LysoTracker-positive vesicles and by delayed phagosome maturation, both of which were observed in Smcr8−/− macrophages. Smcr8−/− mice also showed elevated susceptibility to dextran sodium sulfate-induced colitis, which was not associated with increased TLR3, TLR7, or TLR9 signaling. Deficiency of WDR41 phenocopied loss of SMCR8. Our findings provide evidence that excessive endosomal TLR signaling resulting from prolonged ligand–receptor contact causes inflammatory disease in SMCR8-deficient mice.
6
Tang, Dan, Jingwen Sheng, Liangting Xu, Chuangye Yan e Shiqian Qi. "The C9orf72-SMCR8-WDR41 complex is a GAP for small GTPases". Autophagy 16, n. 8 (17 giugno 2020): 1542–43. http://dx.doi.org/10.1080/15548627.2020.1779473.
7
Fukatsu, Shoya, Hinami Sashi, Remina Shirai, Norio Takagi, Hiroaki Oizumi, Masahiro Yamamoto, Katsuya Ohbuchi, Yuki Miyamoto e Junji Yamauchi. "Rab11a Controls Cell Shape via C9orf72 Protein: Possible Relationships to Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTDALS) Type 1". Pathophysiology 31, n. 1 (9 febbraio 2024): 100–116. http://dx.doi.org/10.3390/pathophysiology31010008.
Abstract (sommario):
Abnormal nucleotide insertions of C9orf72, which forms a complex with Smith–Magenis syndrome chromosomal region candidate gene 8 (SMCR8) protein and WD repeat-containing protein 41 (WDR41) protein, are associated with an autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 1 (FTDALS1). The differentially expressed in normal and neoplastic cells (DENN) domain-containing C9orf72 and its complex with SMCR8 and WDR41 function as a guanine-nucleotide exchange factor for Rab GTP/GDP-binding proteins (Rab GEF, also called Rab activator). Among Rab proteins serving as major effectors, there exists Rab11a. However, it remains to be established which Rab protein is related to promoting or sustaining neuronal morphogenesis or homeostasis. In this study, we describe that the knockdown of Rab11a decreases the expression levels of neuronal differentiation marker proteins, as well as the elongation of neurite-like processes, using N1E-115 cells, a well-utilized neuronal differentiation model. Similar results were obtained in primary cortical neurons. In contrast, the knockdown of Rab11b, a Rab11a homolog, did not significantly affect their cell morphological changes. It is of note that treatment with hesperetin, a citrus flavonoid (also known as Vitamin P), recovered the neuronal morphological phenotypes induced by Rab11a knockdown. Also, the knockdown of Rab11a or Rab11b led to a decrease in glial marker expression levels and in morphological changes in FBD-102b cells, which serve as the oligodendroglial differentiation model. Rab11a is specifically involved in the regulation of neuronal morphological differentiation. The knockdown effect mimicking the loss of function of C9orf72 is reversed by treatment with hesperetin. These findings may reveal a clue for identifying one of the potential molecular and cellular phenotypes underlying FTDALS1.
8
Liu, Kai, Youli Jian, Xiaojuan Sun, Chengkui Yang, Zhiyang Gao, Zhili Zhang, Xuezhao Liu et al. "Negative regulation of phosphatidylinositol 3-phosphate levels in early-to-late endosome conversion". Journal of Cell Biology 212, n. 2 (18 gennaio 2016): 181–98. http://dx.doi.org/10.1083/jcb.201506081.
Abstract (sommario):
Phosphatidylinositol 3-phosphate (PtdIns3P) plays a central role in endosome fusion, recycling, sorting, and early-to-late endosome conversion, but the mechanisms that determine how the correct endosomal PtdIns3P level is achieved remain largely elusive. Here we identify two new factors, SORF-1 and SORF-2, as essential PtdIns3P regulators in Caenorhabditis elegans. Loss of sorf-1 or sorf-2 leads to greatly elevated endosomal PtdIns3P, which drives excessive fusion of early endosomes. sorf-1 and sorf-2 function coordinately with Rab switching genes to inhibit synthesis of PtdIns3P, allowing its turnover for endosome conversion. SORF-1 and SORF-2 act in a complex with BEC-1/Beclin1, and their loss causes elevated activity of the phosphatidylinositol 3-kinase (PI3K) complex. In mammalian cells, inactivation of WDR91 and WDR81, the homologs of SORF-1 and SORF-2, induces Beclin1-dependent enlargement of PtdIns3P-enriched endosomes and defective degradation of epidermal growth factor receptor. WDR91 and WDR81 interact with Beclin1 and inhibit PI3K complex activity. These findings reveal a conserved mechanism that controls appropriate PtdIns3P levels in early-to-late endosome conversion.
9
Snyder, Anthony J., Andrew T. Abad e Pranav Danthi. "A CRISPR-Cas9 screen reveals a role for WD repeat-containing protein 81 (WDR81) in the entry of late penetrating viruses". PLOS Pathogens 18, n. 3 (23 marzo 2022): e1010398. http://dx.doi.org/10.1371/journal.ppat.1010398.
Abstract (sommario):
Successful initiation of infection by many different viruses requires their uptake into the endosomal compartment. While some viruses exit this compartment early, others must reach the degradative, acidic environment of the late endosome. Mammalian orthoreovirus (reovirus) is one such late penetrating virus. To identify host factors that are important for reovirus infection, we performed a CRISPR-Cas9 knockout (KO) screen that targets over 20,000 genes in fibroblasts derived from the embryos of C57/BL6 mice. We identified seven genes (WDR81, WDR91, RAB7, CCZ1, CTSL, GNPTAB, and SLC35A1) that were required for the induction of cell death by reovirus. Notably, CRISPR-mediated KO of WD repeat-containing protein 81 (WDR81) rendered cells resistant to reovirus infection. Susceptibility to reovirus infection was restored by complementing KO cells with human WDR81. Although the absence of WDR81 did not affect viral attachment efficiency or uptake into the endosomal compartments for initial disassembly, it reduced viral gene expression and diminished infectious virus production. Consistent with the role of WDR81 in impacting the maturation of endosomes, WDR81-deficiency led to the accumulation of reovirus particles in dead-end compartments. Though WDR81 was dispensable for infection by VSV (vesicular stomatitis virus), which exits the endosomal system at an early stage, it was required for VSV-EBO GP (VSV that expresses the Ebolavirus glycoprotein), which must reach the late endosome to initiate infection. These results reveal a previously unappreciated role for WDR81 in promoting the replication of viruses that transit through late endosomes.
10
LIU, Nan, e ChongLin YANG. "WDR91-WDR81 complex-dependent endolysosomal trafficking and neural development". SCIENTIA SINICA Vitae 49, n. 7 (1 luglio 2019): 798–805. http://dx.doi.org/10.1360/ssv-2019-0100.
11
Yang, Mei, Chen Liang, Kunchithapadam Swaminathan, Stephanie Herrlinger, Fan Lai, Ramin Shiekhattar e Jian-Fu Chen. "A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy". Science Advances 2, n. 9 (settembre 2016): e1601167. http://dx.doi.org/10.1126/sciadv.1601167.
Abstract (sommario):
The intronic GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a prevalent genetic abnormality identified in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) is a protein with unclear functions. We report that C9ORF72 is a component of a multiprotein complex containing SMCR8, WDR41, and ATG101 (an important regulator of autophagy). The C9ORF72 complex displays guanosine triphosphatase (GTPase) activity and acts as a guanosine diphosphate–guanosine 5′-triphosphate (GDP-GTP) exchange factor (GEF) for RAB39B. We created Smcr8 knockout mice and found that Smcr8 mutant cells exhibit impaired autophagy induction, which is similarly observed in C9orf72 knockdown cells. Mechanistically, SMCR8/C9ORF72 interacts with the key autophagy initiation ULK1 complex and regulates expression and activity of ULK1. The complex has an additional role in regulating later stages of autophagy. Whereas autophagic flux is enhanced in C9orf72 knockdown cells, depletion of Smcr8 results in a reduced flux with an abnormal expression of lysosomal enzymes. Thus, C9ORF72 and SMCR8 have similar functions in modulating autophagy induction by regulating ULK1 and play distinct roles in regulating autophagic flux.
12
Nörpel, Julia, Simone Cavadini, Andreas D. Schenk, Alexandra Graff-Meyer, Daniel Hess, Jan Seebacher, Jeffrey A. Chao e Varun Bhaskar. "Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture". PLOS Biology 19, n. 7 (23 luglio 2021): e3001344. http://dx.doi.org/10.1371/journal.pbio.3001344.
Abstract (sommario):
A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G4C2 repeat expansion in the first intron of the C9orf72 gene. Many underlying mechanisms lead to manifestation of disease that include toxic gain-of-function by repeat G4C2 RNAs, dipeptide repeat proteins, and a reduction of the C9orf72 gene product. The C9orf72 protein interacts with SMCR8 and WDR41 to form a trimeric complex and regulates multiple cellular pathways including autophagy. Here, we report the structure of the C9orf72-SMCR8 complex at 3.8 Å resolution using single-particle cryo-electron microscopy (cryo-EM). The structure reveals 2 distinct dimerization interfaces between C9orf72 and SMCR8 that involves an extensive network of interactions. Homology between C9orf72-SMCR8 and Folliculin-Folliculin Interacting Protein 2 (FLCN-FNIP2), a GTPase activating protein (GAP) complex, enabled identification of a key residue within the active site of SMCR8. Further structural analysis suggested that a coiled-coil region within the uDenn domain of SMCR8 could act as an interaction platform for other coiled-coil proteins, and its deletion reduced the interaction of the C9orf72-SMCR8 complex with FIP200 upon starvation. In summary, this study contributes toward our understanding of the biological function of the C9orf72-SMCR8 complex.
13
Leray, Xavier, Rossella Conti, Yan Li, Cécile Debacker, Florence Castelli, François Fenaille, Anselm A. Zdebik, Michael Pusch e Bruno Gasnier. "Arginine-selective modulation of the lysosomal transporter PQLC2 through a gate-tuning mechanism". Proceedings of the National Academy of Sciences 118, n. 32 (3 agosto 2021): e2025315118. http://dx.doi.org/10.1073/pnas.2025315118.
Abstract (sommario):
Lysosomes degrade excess or damaged cellular components and recycle their building blocks through membrane transporters. They also act as nutrient-sensing signaling hubs to coordinate cell responses. The membrane protein PQ-loop repeat-containing protein 2 (PQLC2; “picklock two”) is implicated in both functions, as it exports cationic amino acids from lysosomes and serves as a receptor and amino acid sensor to recruit the C9orf72/SMCR8/WDR41 complex to lysosomes upon nutrient starvation. Its transport activity is essential for drug treatment of the rare disease cystinosis. Here, we quantitatively studied PQLC2 transport activity using electrophysiological and biochemical methods. Charge/substrate ratio, intracellular pH, and reversal potential measurements showed that it operates in a uniporter mode. Thus, PQLC2 is uncoupled from the steep lysosomal proton gradient, unlike many lysosomal transporters, enabling bidirectional cationic amino acid transport across the organelle membrane. Surprisingly, the specific presence of arginine, but not other substrates (lysine, histidine), in the discharge (“trans”) compartment impaired PQLC2 transport. Kinetic modeling of the uniport cycle recapitulated the paradoxical substrate-yet-inhibitor behavior of arginine, assuming that bound arginine facilitates closing of the transporter’s cytosolic gate. Arginine binding may thus tune PQLC2 gating to control its conformation, suggesting a potential mechanism for nutrient signaling by PQLC2 to its interaction partners.
14
Wada, Kouko, Manae Sato, Nanase Araki, Masahiro Kumeta, Yuya Hirai, Kunio Takeyasu, Kazuhiro Furukawa e Tsuneyoshi Horigome. "Dynamics of WD-repeat containing proteins in SSU processome components". Biochemistry and Cell Biology 92, n. 3 (giugno 2014): 191–99. http://dx.doi.org/10.1139/bcb-2014-0007.
Abstract (sommario):
Nine WD-repeat containing proteins in human SSU processome components have been found in a HeLa cell nuclear matrix fraction. In these proteins, t-UTP sub-complex components, i.e., CIRH1A, UTP15, and WDR43, were shown to be immobilized in the fibrillar centers of nucleoli in living cells. In this study, the dynamics of the remaining six proteins fused with green fluorescent protein (GFP), i.e., PWP2-GFP, TBL3-GFP, GFP-UTP18, GFP-NOL10, GFP-WDR46, and GFP-WDSOF1, were examined in living cells. The findings were as follows. (i) The majority of UTP-B sub-complex components, i.e., PWP2-GFP, TBL3-GFP, and GFP-UTP18, are localized to the dense fibrillar component and granular component regions in nucleoli; (ii) When rRNA transcription is suppressed, the majority of GFP-fused UTP-B sub-complex components are localized in the cap and body regions of nucleoli. (iii) The mobility of these proteins except for GFP-WDSOF1, and half of GFP-UTP18 and GFP-WDR46, respectively, is very low in living cells. (iv) When rRNA transcription is suppressed, the mobility of these proteins except for GFP-WDSOF1 is accelerated but still slow. These findings and others suggest that these WD-repeat proteins other than GFP-WDSOF1 found in the nuclear matrix fraction bind tightly to some macro-protein complexes and act as a scaffold or a core for the complexes in nucleoli.
15
Rapiteanu, Radu, Luther J. Davis, James C. Williamson, Richard T. Timms, J. Paul Luzio e Paul J. Lehner. "A Genetic Screen Identifies a Critical Role for the WDR81‐WDR91 Complex in the Trafficking and Degradation of Tetherin". Traffic 17, n. 8 (25 maggio 2016): 940–58. http://dx.doi.org/10.1111/tra.12409.
16
Liu, Kai, Ruxiao Xing, Youli Jian, Zhiyang Gao, Xinli Ma, Xiaojuan Sun, Yang Li et al. "WDR91 is a Rab7 effector required for neuronal development". Journal of Cell Biology 216, n. 10 (31 agosto 2017): 3307–21. http://dx.doi.org/10.1083/jcb.201705151.
Abstract (sommario):
Early-to-late endosome conversion, which is essential for delivery of endosomal cargoes to lysosomes, requires switching of early endosome–specific Rab5 and PtdIns3P to late endosome–specific Rab7 and PtdIns(3,5)P2. In this study, we identify the WD40-repeat protein WDR91 as a Rab7 effector that couples Rab switching with PtdIns3P down-regulation on endosomes. Loss of WDR91 greatly increases endosomal PtdIns3P levels, arresting endosomes at an intermediate stage and blocking endosomal–lysosomal trafficking. WDR91 is recruited to endosomes by interacting with active guanosine triphosophate–Rab7 and inhibits Rab7-associated phosphatidylinositol 3-kinase activity. In mice, global Wdr91 knockout causes neonatal death, whereas brain-specific Wdr91 inactivation impairs brain development and causes postnatal death. Mouse neurons lacking Wdr91 accumulate giant intermediate endosomes and exhibit reduced neurite length and complexity. These phenotypes are rescued by WDR91 but not WDR91 mutants that cannot interact with Rab7. Thus, WDR91 serves as a Rab7 effector that is essential for neuronal development by facilitating endosome conversion in the endosome–lysosome pathway.
17
Seibler, Philip, Lena F. Burbulla, Marija Dulovic, Simone Zittel, Johanne Heine, Thomas Schmidt, Franziska Rudolph et al. "Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells". Brain 141, n. 10 (30 agosto 2018): 3052–64. http://dx.doi.org/10.1093/brain/awy230.
Abstract (sommario):
Abstract Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells. However, the role of WDR45 in iron homeostasis remains elusive. Here we studied patient-specific WDR45 mutant fibroblasts and induced pluripotent stem cell-derived midbrain neurons. Our data demonstrated that loss of WDR45 increased cellular iron levels and oxidative stress, accompanied by mitochondrial abnormalities, autophagic defects, and diminished lysosomal function. Restoring WDR45 levels partially rescued oxidative stress and the susceptibility to iron treatment, and activation of autophagy reduced the observed iron overload in WDR45 mutant cells. Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function.
18
Aring, Luisa, Eun-kyeong Choi e Young-Ah Seo. "WDR45 Contributes to Iron Accumulation Through Dysregulation of Neuronal Iron Homeostasis". Current Developments in Nutrition 4, Supplement_2 (29 maggio 2020): 1188. http://dx.doi.org/10.1093/cdn/nzaa057_004.
Abstract (sommario):
Abstract Objectives Neurodegeneration with brain iron accumulation (NBIA) is a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by an abnormal accumulation of brain iron and progressive degeneration of the nervous system. β-propeller protein-associated neurodegeneration (BPAN) (OMIM #300,894) is a recently identified subtype of NBIA. BPAN is caused by de novo mutations in the WD repeat domain 45 (WDR45) gene. WDR45 deficiency in BPAN patients and animal models has shown defects in autophagic flux, suggesting a role for WDR45 in autophagy. How WDR45 deficiency leads to brain iron overload remains unclear. The goal of the present study is to identify the pathogenic mechanisms of WDR45 deficiency that cause iron overload and neurodegeneration. Methods To elucidate the role of WDR45 in dopaminergic neuronal cells, we generated a WDR45-knockout (KO) SH-SY5Y cell line by CRISPR/Cas9-mediated genome editing. To identify mechanisms underlying iron homeostasis and transport, we examined two cellular iron acquisition pathways in these cells using radioactive isotope 59Fe: 1) the canonical transferrin-bound iron (TBI) uptake pathway and 2) the nontransferrin-bound iron (NTBI) pathway. Results Loss of WDR45 increased total iron levels with a concomitant increase in the iron storage protein ferritin in neuronal cells. Specifically, WDR45-KO cells preferentially took up NTBI compared to wild-type cells. Concordant with these functional data, the level of divalent metal transporter-1 (DMT1) expression was upregulated in WDR45-KO cells, providing a causal link to iron overload in WDR45 deficiency. In addition, loss of WDR45 led to defects in autophagic flux and impaired ferritinophagy, a lysosomal process that promotes ferritin degradation, suggesting that iron overload is driven by impaired ferritinophagy. Interestingly, WDR45 deficiency increased iron accumulation in the mitochondria, impaired mitochondrial function, and in turn, elevated reactive oxygen species generation. Conclusions Our study provides the first evidence that WDR45 deficiency alters cellular iron acquisition pathways thereby leading to iron accumulation in neuronal cells. These findings will serve as a basis for developing therapeutic strategies for patients with NBIA. Funding Sources NIH, NBIA Disorder Association.
19
Liu, Xuezhao, Yang Li, Xin Wang, Ruxiao Xing, Kai Liu, Qiwen Gan, Changyong Tang et al. "The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy". Journal of Cell Biology 216, n. 5 (12 aprile 2017): 1301–20. http://dx.doi.org/10.1083/jcb.201608039.
Abstract (sommario):
Autophagy-dependent clearance of ubiquitinated and aggregated proteins is critical to protein quality control, but the underlying mechanisms are not well understood. Here, we report the essential role of the BEACH (beige and Chediak–Higashi) and WD40 repeat-containing protein WDR81 in eliminating ubiquitinated proteins through autophagy. WDR81 associates with ubiquitin (Ub)-positive protein foci, and its loss causes accumulation of Ub proteins and the autophagy cargo receptor p62. WDR81 interacts with p62, facilitating recognition of Ub proteins by p62. Furthermore, WDR81 interacts with LC3C through canonical LC3-interacting regions in the BEACH domain, promoting LC3C recruitment to ubiquitinated proteins. Inactivation of LC3C or defective autophagy results in accumulation of Ub protein aggregates enriched for WDR81. In mice, WDR81 inactivation causes accumulation of p62 bodies in cortical and striatal neurons in the brain. These data suggest that WDR81 coordinates p62 and LC3C to facilitate autophagic removal of Ub proteins, and provide important insights into CAMRQ2 syndrome, a WDR81-related developmental disorder.
20
Liu, Xuezhao, Limin Yin, Tianyou Li, Lingxi Lin, Jie Zhang e Yang Li. "Reduction of WDR81 impairs autophagic clearance of aggregated proteins and cell viability in neurodegenerative phenotypes". PLOS Genetics 17, n. 3 (17 marzo 2021): e1009415. http://dx.doi.org/10.1371/journal.pgen.1009415.
Abstract (sommario):
Neurodegenerative diseases are characterized by neuron loss and accumulation of undegraded protein aggregates. These phenotypes are partially due to defective protein degradation in neuronal cells. Autophagic clearance of aggregated proteins is critical to protein quality control, but the underlying mechanisms are still poorly understood. Here we report the essential role of WDR81 in autophagic clearance of protein aggregates in models of Huntington’s disease (HD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In hippocampus and cortex of patients with HD, PD and AD, protein level of endogenous WDR81 is decreased but autophagic receptor p62 accumulates significantly. WDR81 facilitates the recruitment of autophagic proteins onto Htt polyQ aggregates and promotes autophagic clearance of Htt polyQ subsequently. The BEACH and MFS domains of WDR81 are sufficient for its recruitment onto Htt polyQ aggregates, and its WD40 repeats are essential for WDR81 interaction with covalent bound ATG5-ATG12. Reduction of WDR81 impairs the viability of mouse primary neurons, while overexpression of WDR81 restores the viability of fibroblasts from HD patients. Notably, in Caenorhabditis elegans, deletion of the WDR81 homolog (SORF-2) causes accumulation of p62 bodies and exacerbates neuron loss induced by overexpressed α-synuclein. As expected, overexpression of SORF-2 or human WDR81 restores neuron viability in worms. These results demonstrate that WDR81 has crucial evolutionarily conserved roles in autophagic clearance of protein aggregates and maintenance of cell viability under pathological conditions, and its reduction provides mechanistic insights into the pathogenesis of HD, PD, AD and brain disorders related to WDR81 mutations.
21
Kannan, Meghna, Efil Bayam, Christel Wagner, Bruno Rinaldi, Perrine F. Kretz, Peggy Tilly, Marna Roos et al. "WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy". Proceedings of the National Academy of Sciences 114, n. 44 (12 ottobre 2017): E9308—E9317. http://dx.doi.org/10.1073/pnas.1713625114.
Abstract (sommario):
The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.
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Wang, Jie, Xiao-Lin Kou, Cheng Chen, Mei Wang, Cui Qi, Jing Wang, Wei-Yan You, Gang Hu, Jiong Chen e Jun Gao. "Hippocampal Wdr1 Deficit Impairs Learning and Memory by Perturbing F-actin Depolymerization in Mice". Cerebral Cortex 29, n. 10 (22 dicembre 2018): 4194–207. http://dx.doi.org/10.1093/cercor/bhy301.
Abstract (sommario):
Abstract WD repeat protein 1 (Wdr1), known as a cofactor of actin-depolymerizing factor (ADF)/cofilin, is conserved among eukaryotes, and it plays a critical role in the dynamic reorganization of the actin cytoskeleton. However, the function of Wdr1 in the central nervous system remains elusive. Using Wdr1 conditional knockout mice, we demonstrated that Wdr1 plays a significant role in regulating synaptic plasticity and memory. The knockout mice exhibited altered reversal spatial learning and fear responses. Moreover, the Wdr1 CKO mice showed significant abnormalities in spine morphology and synaptic function, including enhanced hippocampal long-term potentiation and impaired long-term depression. Furthermore, we observed that Wdr1 deficiency perturbed actin rearrangement through regulation of the ADF/cofilin activity. Taken together, these results indicate that Wdr1 in the hippocampal CA1 area plays a critical role in actin dynamics in associative learning and postsynaptic receptor availability.
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Diaw, Sokhna Haissatou, Christos Ganos, Simone Zittel, Kirstin Plötze-Martin, Leonora Kulikovskaja, Melissa Vos, Ana Westenberger, Aleksandar Rakovic, Katja Lohmann e Marija Dulovic-Mahlow. "Mutant WDR45 Leads to Altered Ferritinophagy and Ferroptosis in β-Propeller Protein-Associated Neurodegeneration". International Journal of Molecular Sciences 23, n. 17 (23 agosto 2022): 9524. http://dx.doi.org/10.3390/ijms23179524.
Abstract (sommario):
Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) caused by loss-of-function variants in WDR45. The underlying mechanism of iron accumulation in WDR45 deficiency remains elusive. We established a primary skin fibroblast culture of a new BPAN patient with a missense variant p.(Asn61Lys) in WDR45 (NM_007075.3: c.183C>A). The female patient has generalized dystonia, anarthria, parkinsonism, spasticity, stereotypies, and a distinctive cranial MRI with generalized brain atrophy, predominantly of the cerebellum. For the functional characterization of this variant and to provide a molecular link of WDR45 and iron accumulation, we looked for disease- and variant-related changes in the patient’s fibroblasts by qPCR, immunoblotting and immunofluorescence comparing to three controls and a previously reported WDR45 patient. We demonstrated molecular changes in mutant cells comprising an impaired mitochondrial network, decreased levels of lysosomal proteins and enzymes, and altered autophagy, confirming the pathogenicity of the variant. Compared to increased levels of the ferritinophagy marker Nuclear Coactivator 4 (NCOA4) in control cells upon iron treatment, patients’ cells revealed unchanged NCOA4 protein levels, indicating disturbed ferritinophagy. Additionally, we observed abnormal protein levels of markers of the iron-dependent cell death ferroptosis in patients’ cells. Altogether, our data suggests that WDR45 deficiency affects ferritinophagy and ferroptosis, consequentially disturbing iron recycling.
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Huang, Huang, Jidong Yan, Xi Lan, Yuanxu Guo, Mengyao Sun, Yitong Zhao, Fujun Zhang, Jian Sun e Shemin Lu. "LncRNA WDR11-AS1 Promotes Extracellular Matrix Synthesis in Osteoarthritis by Directly Interacting with RNA-Binding Protein PABPC1 to Stabilize SOX9 Expression". International Journal of Molecular Sciences 24, n. 1 (3 gennaio 2023): 817. http://dx.doi.org/10.3390/ijms24010817.
Abstract (sommario):
Osteoarthritis (OA) is a degenerative disease of articular cartilage that is mainly characterized by chronic and mild inflammation of the joints. Recently, many studies have reported the crucial roles of long noncoding RNAs (lncRNAs) in OA as gene transcriptional regulatory factors, diagnostic biomarkers, or therapeutic targets. However, the exact mechanisms of lncRNAs in the regulation of OA progression remain unclear. In the present study, the lncRNA WDR11 divergent transcript (lncRNA WDR11-AS1) was shown to be downregulated in osteoarthritic cartilage tissues from patients, and to promote extracellular matrix (ECM) synthesis in osteoarthritic chondrocytes with knockdown and overexpression experiments. This function of lncRNA WDR11-AS1 was linked to its ability to interact with the polyadenylate-binding protein cytoplasmic 1 (PABPC1), which was screened by RNA pulldown and mass spectrometry analyses. PABPC1 was discovered to bind ECM-related mRNAs such as SOX9, and the inhibition of PABPC1 improved the mRNA stability of SOX9 to mitigate OA progression. Our results suggest that lncRNA WDR11-AS1 has a promising inhibitory effect on inflammation-induced ECM degradation in OA by directly binding PABPC1, thereby establishing lncRNA WDR11-AS1 and PABPC1 as potential therapeutic targets in the treatment of OA.
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Suárez-Carrillo, Alejandra, Mónica Álvarez-Córdoba, Ana Romero-González, Marta Talaverón-Rey, Suleva Povea-Cabello, Paula Cilleros-Holgado, Rocío Piñero-Pérez et al. "Antioxidants Prevent Iron Accumulation and Lipid Peroxidation, but Do Not Correct Autophagy Dysfunction or Mitochondrial Bioenergetics in Cellular Models of BPAN". International Journal of Molecular Sciences 24, n. 19 (26 settembre 2023): 14576. http://dx.doi.org/10.3390/ijms241914576.
Abstract (sommario):
Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate the autophagic defects and secondary pathological consequences in cellular models derived from two patients harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibroblasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. A transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with the accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron accumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochondrial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the expression levels of WDR45, neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidants partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected.
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Taylor, Kathryne E., e Karen L. Mossman. "Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication". Journal of Virology 89, n. 19 (15 luglio 2015): 9841–52. http://dx.doi.org/10.1128/jvi.01705-15.
Abstract (sommario):
ABSTRACTIt has recently been proposed that the herpes simplex virus (HSV) protein ICP0 has cytoplasmic roles in blocking antiviral signaling and in promoting viral replication in addition to its well-known proteasome-dependent functions in the nucleus. However, the mechanisms through which it produces these effects remain unclear. While investigating this further, we identified a novel cytoplasmic interaction between ICP0 and the poorly characterized cellular protein WDR11. During an HSV infection, WDR11 undergoes a dramatic change in localization at late times in the viral replication cycle, moving from defined perinuclear structures to a dispersed cytoplasmic distribution. While this relocation was not observed during infection with viruses other than HSV-1 and correlated with efficient HSV-1 replication, the redistribution was found to occur independently of ICP0 expression, instead requiring viral late gene expression. We demonstrate for the first time that WDR11 is localized to thetrans-Golgi network (TGN), where it interacts specifically with some, but not all, HSV virion components, in addition to ICP0. Knockdown of WDR11 in cultured human cells resulted in a modest but consistent decrease in yields of both wild-type and ICP0-null viruses, in the supernatant and cell-associated fractions, without affecting viral gene expression. Although further study is required, we propose that WDR11 participates in viral assembly and/or secondary envelopment.IMPORTANCEWhile the TGN has been proposed to be the major site of HSV-1 secondary envelopment, this process is incompletely understood, and in particular, the role of cellular TGN components in this pathway is unknown. Additionally, little is known about the cellular functions of WDR11, although the disruption of this protein has been implicated in multiple human diseases. Therefore, our finding that WDR11 is a TGN-resident protein that interacts with specific viral proteins to enhance viral yields improves both our understanding of basic cellular biology as well as how this protein is co-opted by HSV.
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Lin, Chi, Juan Wang, Long Ouyang, Huaxin Duan e Shasha Fan. "WDR4 as a potential indicator of clinical prognosis and immunotherapy in hepatocellular carcinoma." Journal of Clinical Oncology 42, n. 16_suppl (1 giugno 2024): e16275-e16275. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e16275.
Abstract (sommario):
e16275 Background: Immunotherapy has garnered increasing attention in hepatocellular carcinoma (HCC) treatment. However, there remains a pressing need for effective immunological predictive biomarkers. In our previous study, utilizing data extracted from The Cancer Genome Atlas (TCGA) database, we identified a positive correlation between WDR4 expression levels in hepatocellular carcinoma and various clinical parameters, encompassing Stage, T-stage, pathological grade, AFP level, and vascular invasion. Additionally, higher WDR4 expression was linked to poorer prognosis. Leveraging The TIMER and GEPIA databases, we further elucidated a significant association between WDR4 expression levels and the extent of immune cell infiltration, particularly macrophages, B lymphocytes, and myeloid suppressor cells, in hepatocellular carcinoma. These findings propose the potential utility of WDR4 as a biomarker for immune infiltration in hepatocellular carcinoma. As noted in the trial NCT03867084, which hypothesized that adjuvant pembrolizumab might surpass placebo efficacy, there still exists a gap in identifying the specific population benefiting from adjuvant immunotherapy. Methods: Clinical and pathological data from patients who underwent single-agent immunotherapy for HCC were additionally collected from Hunan Provincial People's Hospital between January 1, 2019, and January 31, 2024. These patients participated in the clinical trial (NCT03867084) with informed consent. The relationship between WDR4 expression levels, clinical pathological data, and patient prognosis was assessed using the Kruskal-Wallis test and Kaplan-Meier survival curve analysis. Results: WDR4 displayed significant upregulation in HCC tissues compared to para-carcinoma tissues (P < 0.001) and exhibited robust diagnostic potential. WDR4 expression showed significant associations with various immune cells, including macrophages (r = 0.278, P < 0.001). Kaplan-Meier survival analysis indicated that patients with high WDR4 expression had shorter postoperative progression-free survival in the context of immunotherapy. Data from 37 patients who underwent postoperative single-agent immunotherapy for hepatocellular carcinoma (NCT03867084) revealed a significant correlation between WDR4 expression levels and Disease-Free Survival (DFS), with notable statistical significance (Log-rank P < 0.001). Conclusions: WDR4 demonstrates elevated expression levels within HCC tissues and is associated with immune infiltration, establishing it as a prognostic biomarker in HCC. Furthermore, the positive correlation observed between WDR4 and CD68 as well as PD-L1 underscores its potential as a guiding factor in immunotherapeutic approaches for HCC.
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Dasgupta, Swapan Kumar, Qi Da, Anhquyen Le, Miguel A. Cruz e Perumal Thiagarajan. "Wdr1-Mediated Actin Reorganization Is Essential for Integrin αIIbβ3 Activation in Platelets". Blood 126, n. 23 (3 dicembre 2015): 2231. http://dx.doi.org/10.1182/blood.v126.23.2231.2231.
Abstract (sommario):
Abstract In resting platelets, the heterodimeric integrin αIIbβ3 is present in a low-affinity state. During platelet activation, the intracytoplasmic signals induce conformational changes that results in a swung-out conformation of the extracellular domain competent to bind ligands such as fibrinogen with high affinity to mediate platelet aggregation. Actin turnover is essential for this process and dynamic assembly and disassembly of actin filaments regulate it. We have identified Wdr1, a cofilin and actin binding protein containing WD40 repeats, as an essential component of the machinery that orchestrates actin fiber reorganization that leads to integrin αIIbβ3 activation. Methods: Wdr1-deficient mouse strain, Wdr1rd/rd. was obtained through an N-ethyl-N-nitrosourea mutagenesis screen in Baylor College of Medicine. The mutant mouse has a T>A transversion in the second dinucleotide of the intron 9 splice donor site and it produces a mutant transcript containing a 6-bp in-frame deletion that results in a incorrectly folded, nonfunctional protein. Normal splicing produces a small amount of Wdr1 protein (~2%) resulting in a hypomorphic allele. Wdr1-deficient mice are moderately thrombocytopenic (85± 11 x 106 ml Wdr1 deficient versus 427± 52 x 106/ml for wild-type). Platelets were isolated from Wdr1-deficient and control mice. Platelet aggregation was carried out by standard turbidometric methods. Calcium mobilization was measured by incubating Wdr1-deficient and WT (wild-type) platelets with Fura 2 AM and measuring the Fura 2 fluorescence after collagen treatment. Conformational change in αIIbβ3 was determined by flow cytometry with a conformation-specific anti-αIIbβ3 antibody JON/A. In vivo hemostasis was assessed by tail bleeding time and FeCl3-induced endothelial carotid injury/thrombosis model was used to assess the occlusion in carotid artery of mice. Results: Aggregation response of Wdr1-deficient platelets to different doses of collagen was significantly impaired compared to WT platelets. Under similar conditions, the calcium response was similar to the WT. In a parallel-plate flow chamber assay, WT platelets stably adhered to collagen surface and formed stable thrombus. On the other hand, significantly less number of Wdr1 deficient platelets were stably attach to the collagen surface and it did not form stable thrombus. As expected the tail bleeding time of Wdr1 deficient mice is significantly prolonged (> 10 minutes) compared to WT mice (<2 min). In vivo, in FeCl3 induced carotid artery thrombosis model, vessel occlusion in Wdr1 deficient was prolonged significantly compared wild type mice (15.8 ± 12.6 minutes versus 9.0 ± 10.5 minutes (p=0.041, Mann-Whitney non parametric comparison). To examine directly the activation of αIIbβ3, we used JON/A antibody, which selectively binds to activated αIIbβ3 integrins on mouse platelets. Binding of collagen treated Wdr1-deficient platelets to JON/A as determined by flow cytometry, is significantly less compared to WT platelets (6.1±0.3 fluorescence units (FU) versus 17.4±0.6 FU, p≤0.05) indicating impaired inside-out activation of αIIbβ3. Since, Wdr1 promotes actin disassembly, which is essential for the rearrangement of the actin fibers that occurs during platelet activation, we measured actin turn over by measuring F-actin and G-actin ratios of collagen treated platelets at various time points. Actin turnover is highly impaired in Wdr1 deficient platelets compared to WT platelets. Furthermore, integrin αIIbβ3 association with actin cytoskeleton was markedly impaired in Wdr1 deficient mice compared to their WT controls. These studies show that Wdr1 mediated actin cytoskeleton reorganization is essential for integrin αIIbβ3 activation. Disclosures No relevant conflicts of interest to declare.
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Jussara Maria Gonçalves, João Luiz Dornelles Bastos, Elena Riet Correa Rivero e Mabel Mariela Rodríguez Cordeiro. "Immunoexpression of tumor suppressor protein p53 and deubiquitinating enzymes in oral squamous cell carcinoma". RSBO 19, n. 1 (6 giugno 2022): 10–07. http://dx.doi.org/10.21726/rsbo.v19i1.1753.
Abstract (sommario):
The ubiquitin-proteasome system is regulated by deubiquitinating enzymes (DUBs), which include the complex Ubiquitin-specific protease 1 (USP1) and WD40 repeat-containing protein 48 (WDR48). In normal conditions, these proteins contribute to genome integrity by regulating the DNA repair pathways. However, studies have associated abnormalities in this complex with the pathogenesis of cancer. Simultaneously, Tumor Suppressor Protein p53 is also regulated by ubiquitin-dependent degradation and its overexpression suggests that several DUBs are interacting and deubiquitinating this protein. Objective: To evaluate the immunoexpression of p53, USP1, and WDR48 in Oral Squamous Cell Carcinoma (OSCC). Material and methods: Thirty cases of OSCC and 40 non-neoplastic oral epithelium (NNOE, control group) were selected for immunohistochemical investigation. The histopathological classification was performed using H&E-stained sections. Values were statistically analyzed using the non-parametric test Kruskal Wallis. Results: Higher positivity of the markers was found in OSCC (p53:65%; USP1:96.4%; WDR48: 68.9%) than in NNOE (p53:35.1%; USP1:85%; WDR48: 65.2%). Poorly-differentiated cases of OSCC exhibited higher nuclear immunostaining of all proteins when compared with well-differentiated samples. Conclusion: This is a pioneer study and suggests that p53 and deubiquitinating enzymes (USP1 and WDR48) can affect the biological behavior of OSCC as they are related to the tumor development and histological malignancy grading.
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Wang, Yu-Jia, Eko Mugiyanto, Yun-Ting Peng, Wan-Chen Huang, Wan-Hsuan Chou, Chi-Chiu Lee, Yu-Shiuan Wang et al. "Genetic Association of the Functional WDR4 Gene in Male Fertility". Journal of Personalized Medicine 11, n. 8 (30 luglio 2021): 760. http://dx.doi.org/10.3390/jpm11080760.
Abstract (sommario):
Infertility is one of the important problems in the modern world. Male infertility is characterized by several clinical manifestations, including low sperm production (oligozoospermia), reduced sperm motility (asthenozoospermia), and abnormal sperm morphology (teratozoospermia). WDR4, known as Wuho, controls fertility in Drosophila. However, it is unclear whether WDR4 is associated with clinical manifestations of male fertility in human. Here, we attempted to determine the physiological functions of WDR4 gene. Two cohorts were applied to address this question. The first cohort was the general population from Taiwan Biobank. Genomic profiles from 68,948 individuals and 87 common physiological traits were applied for phenome-wide association studies (PheWAS). The second cohort comprised patients with male infertility from Wan Fang Hospital, Taipei Medical University. In total, 81 male participants were recruited for the genetic association study. Clinical records including gender, age, total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total sperm number, sperm motility, and sperm morphology were collected. In the first cohort, results from PheWAS exhibited no associations between WDR4 genetic variants and 87 common physiological traits. In the second cohort, a total of four tagging single-nucleotide polymorphisms (tSNPs) from WDR4 gene (rs2298666, rs465663, rs2248490, and rs3746939) were selected for genotyping. We found that SNP rs465663 solely associated with asthenozoospermia. Functional annotations through the GTEx portal revealed the correlation between TT or TC genotype and low expression of WDR4. Furthermore, we used mouse embryonic fibroblasts cells from mwdr4 heterozygous (+/‒) mice for functional validation by western blotting. Indeed, low expression of WDR4 contributed to ROS-induced DNA fragmentation. In conclusion, our results suggest a critical role of WDR4 gene variant as well as protein expression in asthenozoospermia.
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Bowes, Charnese, Michael Redd, Malika Yousfi, Muriel Tauzin, Emi Murayama e Philippe Herbomel. "Coronin 1A depletion restores the nuclear stability and viability of Aip1/Wdr1-deficient neutrophils". Journal of Cell Biology 218, n. 10 (30 agosto 2019): 3258–71. http://dx.doi.org/10.1083/jcb.201901024.
Abstract (sommario):
Actin dynamics is central for cells, and especially for the fast-moving leukocytes. The severing of actin filaments is mainly achieved by cofilin, assisted by Aip1/Wdr1 and coronins. We found that in Wdr1-deficient zebrafish embryos, neutrophils display F-actin cytoplasmic aggregates and a complete spatial uncoupling of phospho-myosin from F-actin. They then undergo an unprecedented gradual disorganization of their nucleus followed by eruptive cell death. Their cofilin is mostly unphosphorylated and associated with F-actin, thus likely outcompeting myosin for F-actin binding. Myosin inhibition reproduces in WT embryos the nuclear instability and eruptive death of neutrophils seen in Wdr1-deficient embryos. Strikingly, depletion of the main coronin of leukocytes, coronin 1A, fully restores the cortical location of F-actin, nuclear integrity, viability, and mobility of Wdr1-deficient neutrophils in vivo. Our study points to an essential role of actomyosin contractility in maintaining the integrity of the nucleus of neutrophils and a new twist in the interplay of cofilin, Wdr1, and coronin in regulating F-actin dynamics.
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Montenont, Emilie, Christina Echagarruga, Nicole Allen, Elisa Araldi, Yajaira Suarez e Jeffrey S. Berger. "Platelet WDR1 suppresses platelet activity and is associated with cardiovascular disease". Blood 128, n. 16 (20 ottobre 2016): 2033–42. http://dx.doi.org/10.1182/blood-2016-03-703157.
Abstract (sommario):
Key Points Platelet transcription of WDR1 suppresses platelet activity. Reduced transcription of WDR1 in platelets may be a link between elevated platelet activity and increased risk of cardiovascular disease.
33
Zhu, Jinhong, Xiaoping Liu, Wei Chen, Yuxiang Liao, Jiabin Liu, Li Yuan, Jichen Ruan e Jing He. "Association of RNA m7G Modification Gene Polymorphisms with Pediatric Glioma Risk". BioMed Research International 2023 (24 gennaio 2023): 1–10. http://dx.doi.org/10.1155/2023/3678327.
Abstract (sommario):
Glioma stemming from glial cells of the central nervous system (CNS) is one of the leading causes of cancer death in childhood. The genetic predisposition of glioma is not fully understood. METTL1-WDR4 methyltransferase complex is implicated in tumorigenesis by catalyzing N7-methylguanosine (m7G) modification of RNA. This study is aimed at determining the association of glioma risk with three polymorphisms (rs2291617, rs10877013, and rs10877012) in METTL1 and five polymorphisms (rs2156315 rs2156316, rs6586250, rs15736, and rs2248490) in WDR4 gene in children of Chinese Han. We enrolled 314 cases and 380 controls from three independent hospitals. Genotypes of these polymorphisms were determined using the TaqMan assay. We found the WDR4 gene rs15736 was significantly associated with reduced glioma risk (GA/AA vs. GG: adjusted odds ratio = 0.63 , 95 % confidence interval = 0.42 − 0.94 , P = 0.023 ) out of the eight studied polymorphisms. Stratified analyses showed that the association of rs15736 with the risk of glioma remained significant in children aged 60 months or older, girls, the subgroups with astrocytic tumors, or grade I + II glioma. We also found the combined effects of five WDR4 gene polymorphisms on glioma risk. Finally, expression quantitative trait locus (eQTL) analyses elucidated that the rs15736 polymorphism was related to the expression level of WDR4 and neighboring gene cystathionine-beta-synthase (CBS). Our finding provided evidence of a causal association between WDR4 gene polymorphisms and glioma susceptibility in Chinese Han children.
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Kile, Benjamin T., Athanasia D. Panopoulos, Roslynn A. Stirzaker, Douglas F. Hacking, Lubna H. Tahtamouni, Tracy A. Willson, Lisa A. Mielke et al. "Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia". Blood 110, n. 7 (1 ottobre 2007): 2371–80. http://dx.doi.org/10.1182/blood-2006-10-055087.
Abstract (sommario):
A pivotal mediator of actin dynamics is the protein cofilin, which promotes filament severing and depolymerization, facilitating the breakdown of existing filaments, and the enhancement of filament growth from newly created barbed ends. It does so in concert with actin interacting protein 1 (Aip1), which serves to accelerate cofilin's activity. While progress has been made in understanding its biochemical functions, the physiologic processes the cofilin/Aip1 complex regulates, particularly in higher organisms, are yet to be determined. We have generated an allelic series for WD40 repeat protein 1 (Wdr1), the mammalian homolog of Aip1, and report that reductions in Wdr1 function produce a dramatic phenotype gradient. While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles. Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding. Autoinflammatory disease, which is bone marrow–derived yet nonlymphoid in origin, is characterized by a massive infiltration of neutrophils into inflammatory lesions. Cytoskeletal responses are impaired in Wdr1 mutant neutrophils. These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types.
35
Choi, Jin-Tae, Yeseul Choi, Yujin Lee, Seung-Heon Lee, Seun Kang, Kyung-Tae Lee e Yong-Sun Bahn. "The hybrid RAVE complex plays V-ATPase-dependent and -independent pathobiological roles in Cryptococcus neoformans". PLOS Pathogens 19, n. 10 (9 ottobre 2023): e1011721. http://dx.doi.org/10.1371/journal.ppat.1011721.
Abstract (sommario):
V-ATPase, which comprises 13–14 subunits, is essential for pH homeostasis in all eukaryotes, but its proper function requires a regulator to assemble its subunits. While RAVE (regulator of H+-ATPase of vacuolar and endosomal membranes) and Raboconnectin-3 complexes assemble V-ATPase subunits in Saccharomyces cerevisiae and humans, respectively, the function of the RAVE complex in fungal pathogens remains largely unknown. In this study, we identified two RAVE complex components, Rav1 and Wdr1, in the fungal meningitis pathogen Cryptococcus neoformans, and analyzed their roles. Rav1 and Wdr1 are orthologous to yeast RAVE and human Rabconnectin-3 counterparts, respectively, forming the hybrid RAVE (hRAVE) complex. Deletion of RAV1 caused severe defects in growth, cell cycle control, morphogenesis, sexual development, stress responses, and virulence factor production, while the deletion of WDR1 resulted in similar but modest changes, suggesting that Rav1 and Wdr1 play central and accessary roles, respectively. Proteomics analysis confirmed that Wdr1 was one of the Rav1-interacting proteins. Although the hRAVE complex generally has V-ATPase-dependent functions, it also has some V-ATPase-independent roles, suggesting a unique role beyond conventional intracellular pH regulation in C. neoformans. The hRAVE complex played a critical role in the pathogenicity of C. neoformans, and RAV1 deletion attenuated virulence and impaired blood-brain barrier crossing ability. This study provides comprehensive insights into the pathobiological roles of the fungal RAVE complex and suggests a novel therapeutic strategy for controlling cryptococcosis.
36
Dogrusöz, Mehmet, Andrea Ruschel Trasel, Jinfeng Cao, Selҫuk Ҫolak, Sake I. van Pelt, Wilma G. M. Kroes, Amina F. A. S. Teunisse et al. "Differential Expression of DNA Repair Genes in Prognostically-Favorable versus Unfavorable Uveal Melanoma". Cancers 11, n. 8 (2 agosto 2019): 1104. http://dx.doi.org/10.3390/cancers11081104.
Abstract (sommario):
Expression of DNA repair genes was studied in uveal melanoma (UM) in order to identify genes that may play a role in metastases formation. We searched for genes that are differentially expressed between tumors with a favorable and unfavorable prognosis. Gene-expression profiling was performed on 64 primary UM from the Leiden University Medical Center (LUMC), Leiden, The Netherlands. The expression of 121 genes encoding proteins involved in DNA repair pathways was analyzed: a total of 44 genes differed between disomy 3 and monosomy 3 tumors. Results were validated in a cohort from Genoa and Paris and the The Cancer Genome Atlas (TCGA) cohort. Expression of the PRKDC, WDR48, XPC, and BAP1 genes was significantly associated with clinical outcome after validation. PRKDC was highly expressed in metastasizing UM (p < 0.001), whereas WDR48, XPC, and BAP1 were lowly expressed (p < 0.001, p = 0.006, p = 0.003, respectively). Low expression of WDR48 and XPC was related to a large tumor diameter (p = 0.01 and p = 0.004, respectively), and a mixed/epithelioid cell type (p = 0.007 and p = 0.03, respectively). We conclude that the expression of WDR48, XPC, and BAP1 is significantly lower in UM with an unfavorable prognosis, while these tumors have a significantly higher expression of PRKDC. Pharmacological inhibition of DNA-PKcs resulted in decreased survival of UM cells. PRKDC may be involved in proliferation, invasion and metastasis of UM cells. Unraveling the role of DNA repair genes may enhance our understanding of UM biology and result in the identification of new therapeutic targets.
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Suh, Myung Whan, Dong Hoon Shin, Ho Sun Lee, Ji Yeong Park, Chong Sun Kim e Seung Ha Oh. "WDR1 expression in the normal and noise-damaged chick vestibule". Journal of Vestibular Research 17, n. 4 (1 aprile 2008): 163–70. http://dx.doi.org/10.3233/ves-2007-17402.
Abstract (sommario):
Unlike mammals, avian cochlear hair cells can regenerate after acoustic overstimulation. The WDR1 gene is one of the genes suspected to play an important role in this difference. In an earlier study, we found that the WDR1 gene is over-expressed in the chick cochlea after acoustic overstimulation. The aim of this study was to compare the expression of WDR1 before and after acoustic overstimulation in the chick vestibule. Seven-day-old chicks were divided into three groups: normal group, damage group, and regeneration group. The damage and regeneration group was exposed to 120 dB SPL white noise for 5–6 hours. The damage group was euthanized shortly after the impulse, but the regeneration group was allowed to recover for 2 days. The utricle, saccule, and the three ampullae of each semicircular canal were dissected and immunohistochemically stained with anti-WD40 repeat protein 1 antibody. For quantitative analysis, immunoreactive densities were measured and quantitative real-time RT PCR was performed. WD40 repeat protein 1 expression was elevated in all the semicircular canals and utricle, two days after an acoustic overstimulation (P = 0.001). WDR1 mRNA expression was 1.34 times higher in the regeneration group compared to the normal group, but it was not statistically significant. Exceptionally, WD40 repeat protein 1 expression did not increase in the saccule of the regeneration group. Elevated WDR1 expression in the avian vestibule may have a role in the hair cell regenerating ability as in the avian cochlea. A similar mechanism of hair cell regeneration may exist in the avian cochlea and vestibule.
38
Nagappa, Madhu, Parayil S. Bindu, Sanjib Sinha, Rose D. Bharath, Mangalore Sandhya, Jitender Saini, Pavagada S. Mathuranath e Arun B. Taly. "Palatal Tremor Revisited: Disorder with Nosological Diversity and Etiological Heterogeneity". Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, n. 2 (18 dicembre 2017): 243–47. http://dx.doi.org/10.1017/cjn.2017.273.
Abstract (sommario):
AbstractThis case series aimed to describe clinicoradiological, electromyographic, and etiological spectra in palatal tremor (essential=1; symptomatic=26). Patients with symptomatic palatal tremor had 2 to 10 Hz arrhythmic electromyographic bursts, a spectrum of changes in inferior olivary nucleus, with/without lesions in Guillain Mollaret triangle, and varied etiologies (genetic=9, vascular=6, trauma=3, infections=3). Exome sequencing showed variations in POLG, WDR81, NDUFS8, TENM4, and EEF2. Clinical phenotypes of patients with POLG, WDR81, and NDUFS8 variations were consistent with that described in literature. We highlight salient magnetic resonance imaging features, electrophysiological observations, and diverse etiologies in a large cohort of palatal tremor.
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Standing, Ariane S. I., Dessislava Malinova, Ying Hong, Julien Record, Dale Moulding, Michael P. Blundell, Karolin Nowak et al. "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1". Journal of Experimental Medicine 214, n. 1 (19 dicembre 2016): 59–71. http://dx.doi.org/10.1084/jem.20161228.
Abstract (sommario):
The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1. We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18–binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1. Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation.
40
Lee, Hye Eun, Min Kyo Jung, Seul Gi Noh, Hye Bin Choi, Se hyun Chae, Jae Hyeok Lee e Ji Young Mun. "Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts". International Journal of Molecular Sciences 22, n. 21 (28 ottobre 2021): 11650. http://dx.doi.org/10.3390/ijms222111650.
Abstract (sommario):
Iron overload in the brain, defined as excess stores of iron, is known to be associated with neurological disorders. In neurodegeneration accompanied by brain iron accumulation, we reported a specific point mutation, c.974-1G>A in WD Repeat Domain 45 (WDR45), showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on cellular organelles, including lipid droplets, mitochondria and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria and increased numbers of lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. Based on correlative light and electron microscopy (CLEM) findings, most of the iron accumulation was noted in the lysosomal vesicles. These changes were associated with defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed remarkable changes in lipid metabolism, mitochondrial function, and autophagy-related genes. These data suggested that functional and structural changes resulted in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, caused by iron overload.
41
Dubner, R., D. R. Kenshalo, W. Maixner, M. C. Bushnell e J. L. Oliveras. "The correlation of monkey medullary dorsal horn neuronal activity and the perceived intensity of noxious heat stimuli". Journal of Neurophysiology 62, n. 2 (1 agosto 1989): 450–57. http://dx.doi.org/10.1152/jn.1989.62.2.450.
Abstract (sommario):
1. We examined the relationship between the activity of medullary dorsal horn nociceptive neurons and the monkeys' ability to detect noxious heat stimuli. In two different detection tasks, the temperature of a contact thermode positioned on the monkey's face increased from 38 degrees C to temperatures between 44 and 48 degrees C (T1). After a variable time period, the thermode temperature increased an additional 0.2-1.5 degrees C (T2), and the monkeys' detection speed from the onset of T2 was determined. We previously have established that detection speed is a measure of the perceived intensity of noxious thermal stimuli. Nociceptive neurons were classified as wide-dynamic-range (WDR, responsive to innocuous mechanical stimuli with greater responses to noxious mechanical stimuli) and nociceptive-specific (NS, responsive only to noxious stimuli). WDR neurons were subclassified as WDR1 and WDR2 based on the higher slope values of the stimulus-response functions of WDR1 neurons. The monkeys were trained to detect small increases in noxious heat, and their detection speeds were correlated with the responses of WDR1, WDR2, and NS neurons. 2. Detection speeds to T2 temperatures of 1.0 degrees C from preceding T1 temperatures of 45 and 46 degrees C were faster during a preceding ascending series of stimuli than during a descending series. Similarly, the peak discharge frequencies of WDR1 neurons in response to the same stimuli were greater during the ascending series of T2 temperatures. In contrast, the responses of WDR2 and NS neurons showed no significant differences during the ascending and descending series of stimuli. 3. Detection speeds following 0.4, 0.6, and 0.8 degrees C T2 stimuli were higher when the preceding T1 temperature was 46 degrees C as compared with detection speeds to the identical stimuli when the preceding T1 temperature was 45 degrees C. WDR1 neurons also exhibited a significant increase in peak discharge frequency to these same T2 stimuli when the preceding T1 temperature was 46 degrees C. In contrast, the neuronal activity of WDR2 and NS neurons did not differ on 45 and 46 degrees C T1 trials. 4. The relationship between detection speed and neuronal peak discharge frequency was examined in response to different pairs of T1 and T2 stimuli when T1 was either 45 or 46 degrees C. There was a significant correlation between detection speed and neuronal discharge for WDR1 and WDR2 neurons. No correlation was observed for NS neurons. 5. The magnitude of neuronal activity on correctly detected and nondetected trials was compared when T1 was 46 degrees C and T2 was 0.2 degree C.(ABSTRACT TRUNCATED AT 400 WORDS)
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Chudler, E. H., F. Anton, R. Dubner e D. R. Kenshalo. "Responses of nociceptive SI neurons in monkeys and pain sensation in humans elicited by noxious thermal stimulation: effect of interstimulus interval". Journal of Neurophysiology 63, n. 3 (1 marzo 1990): 559–69. http://dx.doi.org/10.1152/jn.1990.63.3.559.
Abstract (sommario):
1. Twenty-six nociceptive neurons in the primary somatosensory cortex (SI) of anesthetized monkeys were responsive to noxious thermal stimulation applied to the face. Thermode temperature increased from a base line of 38 degrees C to temperatures ranging from 44 to 49 degrees C (T1). After a period of 5 s, the temperature increased an additional 1 degree C (T2). The neuronal responses to noxious thermal stimuli were compared when the interstimulus interval (ISI) was 30 or 180 s. 2. A linear regression analysis was applied to the stimulus-response functions of neuronal responses to T1 stimuli obtained at ISIs of 180 s. Based on the slopes and linear regression coefficients of these stimulus-response functions, two populations of nociceptive neurons were identified. The neuronal responses of one population of nociceptive SI neurons (WDR1) to T1 stimuli were characterized by steep slopes and high regression coefficients, whereas the other population (WDR2) had flatter slopes and lower regression coefficients. WDR1 neurons responded with monotonic increases in neuronal activity as the stimulus intensity increased. However, the peak frequency of WDR2 neurons often reached a plateau below 47 degrees C. Both WDR1 and WDR2 neurons had receptive fields that encompassed one or two divisions of the trigeminal nerve. 3. The T1 neuronal responses of WDR1 neurons were significantly suppressed when thermal stimuli were delivered with ISIs of 30 s. The T1 neuronal responses of WDR2 and the T2 responses of both WDR1 and WDR2 neurons were not significantly different when ISIs of 30 and 180 s were used. The T1 thresholds of WDR1 and WDR2 neurons were significantly higher when stimuli were delivered with ISIs of 30 s compared with ISIs of 180 s. 4. Most nociceptive SI neurons were located in layers III and IV of area 1-2. In a number of instances, multiple nociceptive neurons were found in the same microelectrode penetration. 5. The humans' intensity of pain sensation paralleled the neuronal responses of nociceptive SI neurons. With the use of a similar paradigm as in the monkey experiments, increases in T1 and T2 temperatures resulted in monotonic increases in pain ratings and change in pain sensation, respectively. However, the intensity of pain sensation to T1 temperatures was suppressed by ISIs of 30 s. Neither ISI produced statistically significant changes in the intensity of pain sensation to T2 stimuli. 6. These data demonstrate that manipulations that alter the intensity of pain sensation also produce concomitant changes in the responsiveness of nociceptive SI neurons.(ABSTRACT TRUNCATED AT 400 WORDS)
43
Kuhns, Douglas B., Danielle L. Fink, Uimook Choi, Colin Sweeney, Karen Lau, Debra Long Priel, Dara Riva et al. "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency". Blood 128, n. 17 (27 ottobre 2016): 2135–43. http://dx.doi.org/10.1182/blood-2016-03-706028.
44
Adang, Laura A., Amy Pizzino, Alka Malhotra, Holly Dubbs, Catherine Williams, Omar Sherbini, Anna-Kaisa Anttonen et al. "Phenotypic and Imaging Spectrum Associated With WDR45". Pediatric Neurology 109 (agosto 2020): 56–62. http://dx.doi.org/10.1016/j.pediatrneurol.2020.03.005.
45
Maixner, W., R. Dubner, D. R. Kenshalo, M. C. Bushnell e J. L. Oliveras. "Responses of monkey medullary dorsal horn neurons during the detection of noxious heat stimuli". Journal of Neurophysiology 62, n. 2 (1 agosto 1989): 437–49. http://dx.doi.org/10.1152/jn.1989.62.2.437.
Abstract (sommario):
1. We examined the activity of thermally sensitive trigeminothalamic neurons and nonprojection neurons in the medullary dorsal horn (trigeminal nucleus caudalis) in three monkeys performing thermal and visual detection tasks. 2. An examination of neuronal stimulus-response functions, obtained during thermal-detection tasks in which noxious heat stimuli were applied to the face, indicated that wide-dynamic-range neurons (WDR, responsive to innocuous mechanical stimuli with greater responses to noxious mechanical stimuli) could be subclassified based on the slope values of linear regression lines. WDR1 neurons exhibited significantly greater sensitivity to noxious heat stimulation than WDR2 neurons or nociceptive-specific neurons (NS, responsive only to noxious stimuli). 3. In one behavioral task, the monkeys detected 1.0 degrees C increases in noxious heat from preceding noxious heat stimuli ranging from 44 to 48 degrees C. WDR1, WDR2, and NS neurons increased their discharge frequency as a function of the intensity of the first noxious heat temperature (T1) as well as the final temperature (T2). The responses of WDR1 neurons were greater than those produced by WDR2 or NS neurons across all the temperatures examined. The order of stimulus presentation affected the responses of WDR1 neurons to 1.0 degrees C increases in the noxious heat range but not those of WDR2 or NS neurons. 4. In a second behavioral task, the monkeys detected small increases in noxious heat (0.2-0.8 degrees C) from a first temperature of 46 degrees C. Although the responses of all three classes of neurons were monotonically related to stimulus intensity, WDR1 neurons exhibited greater sensitivity to small temperature increases than either WDR2 or NS neurons. 5. Subpopulations of all three classes of neurons exhibited responses that were independent of thermal stimulus parameters or sensory modality and that only occurred during the behavioral task. These task-related responses were time-locked to specific behavioral events associated with trial initiation and trial continuation. 6. These data provide evidence that a subpopulation of WDR neurons is the dorsal horn cell type most sensitive to small increases in noxious heat in the 45-49 degrees C temperature range and provides the most information about stimulus intensity. The findings support the view that nociceptive neurons have the capacity to precisely encode stimulus features in the noxious range and that WDR neurons are likely to participate in the monkeys' ability to perceive the intensity of such stimuli.
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Fujibuchi, Taketsugu, Yasuhito Abe, Takashi Takeuchi, Yoshinori Imai, Yoshiaki Kamei, Ryuichi Murase, Norifumi Ueda, Kazuhiro Shigemoto, Haruyasu Yamamoto e Katsumi Kito. "AIP1/WDR1 supports mitotic cell rounding". Biochemical and Biophysical Research Communications 327, n. 1 (febbraio 2005): 268–75. http://dx.doi.org/10.1016/j.bbrc.2004.11.156.
47
Curtis, Claire, Jane F. Apperley, Raymond Dang, Michael Jeng, Jason Gotlib, Nicholas C. P. Cross e Francis H. Grand. "The Platelet-Derived Growth Factor Receptor beta Fuses to Two Distinct Loci at 3p21 in Imatinib Responsive Chronic Eosinophilic Leukemia." Blood 106, n. 11 (16 novembre 2005): 3253. http://dx.doi.org/10.1182/blood.v106.11.3253.3253.
Abstract (sommario):
Abstract We have identified three patients (2 adults, one infant) who presented with BCR-ABL negative eosinophilic myeloproliferative disorders. Cytogenetic analysis revealed a t(1;3;5)(p36;p21;q33) for case 1 and a t(3;5)(p21–25;q31–35) for cases 2 and 3. Two-color fluorescence in situ hybridization (FISH) using differentially labelled probes flanking PDGFRB indicated that this gene was disrupted in all three cases. 5′ rapid amplification of cDNA ends (5′RACE) for case 1 identified an in-frame mRNA fusion of exon 9 of the WDR48 gene at 3p21 to exon 12 of PDGFRB. The chimeric mRNA is predicted to encode a 872 amino acid fusion protein that retains the amino terminal WD repeat region of WDR48 fused to the transmembrane and intracellular tyrosine kinase domains of PDGFRbeta. Cases 2 and 3 were negative for the WDR48-PDGFRB fusion mRNA by RT-PCR using several combinations of primers. 5′RACE PCR from case 2 RNA identified a fusion involving a second 3p21 gene: GOLGA4 exon 11 was fused in-frame to exon 11 of PDGFRB. Exactly the same fusion was found in case 3. The predicted 991 amino acid protein included the amino terminal coiled-coil domain of GOLGA4 fused to the transmembrane and intracellular tyrosine kinase domains of PDGFRbeta. Interestingly, both WDR48 and GOLGA4 are involved in endocytic shuttling pathways. The presence of all fusions was confirmed by RT-PCR and identification of the genomic breakpoints. Imatinib, a known inhibitor of PDGFRbeta, selectively blocked the growth of patient CFU-GM for case 2. Following the identification of PDGFRB rearrangements, all three patients were treated with imatinib. Case 1 was in transformation, but responded rapidly to minimal doses of imatinib (800mg daily for 4 days) with complete cytogenetic remission but remained pancytopenic. Blast crisis recurred 8 months later, responded similarly to 3 days of imatinib, but the patient died 2 months later of invasive fungal infection. Case 2 responded clinically and remains in sustained cytogenetic and molecular remission (nested RT-PCR negative for GOLGA4-PDGFRB). Case 3 (a 13 month old boy) had a complete hematologic response to 50mg/day imatinib but the t(3;5) was still seen in 40% of metaphases at 3 months. We conclude that PDGFRB fuses to diverse partner genes to give rise to atypical MPDs. Although very rare, identification of these fusions is critical for proper management of affected individuals.
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Fujimura, Akiko, Yuki Hayashi, Kazashi Kato, Yuichiro Kogure, Mutsuro Kameyama, Haruka Shimamoto, Hiroaki Daitoku, Akiyoshi Fukamizu, Toru Hirota e Keiji Kimura. "Identification of a novel nucleolar protein complex required for mitotic chromosome segregation through centromeric accumulation of Aurora B". Nucleic Acids Research 48, n. 12 (1 giugno 2020): 6583–96. http://dx.doi.org/10.1093/nar/gkaa449.
Abstract (sommario):
Abstract The nucleolus is a membrane-less nuclear structure that disassembles when cells undergo mitosis. During mitosis, nucleolar factors are thus released from the nucleolus and dynamically change their subcellular localization; however, their functions remain largely uncharacterised. Here, we found that a nucleolar factor called nucleolar protein 11 (NOL11) forms a protein complex with two tryptophan-aspartic acid (WD) repeat proteins named WD-repeat protein 43 (WDR43) and Cirhin in mitotic cells. This complex, referred to here as the NWC (NOL11-WDR43-Cirhin) complex, exists in nucleoli during interphase and translocates to the periphery of mitotic chromosomes, i.e., perichromosomal regions. During mitotic progression, both the congression of chromosomes to the metaphase plate and sister chromatid cohesion are impaired in the absence of the NWC complex, as it is required for the centromeric enrichment of Aurora B and the associating phosphorylation of histone H3 at threonine 3. These results reveal the characteristics of a novel protein complex consisting of nucleolar proteins, which is required for regulating kinetochores and centromeres to ensure faithful chromosome segregation.
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Cevik, Sebiha, Xiaoyu Peng, Tina Beyer, Mustafa S. Pir, Ferhan Yenisert, Franziska Woerz, Felix Hoffmann et al. "WDR31 displays functional redundancy with GTPase-activating proteins (GAPs) ELMOD and RP2 in regulating IFT complex and recruiting the BBSome to cilium". Life Science Alliance 6, n. 8 (19 maggio 2023): e202201844. http://dx.doi.org/10.26508/lsa.202201844.
Abstract (sommario):
The correct intraflagellar transport (IFT) assembly at the ciliary base and the IFT turnaround at the ciliary tip are key for the IFT to perform its function, but we still have poor understanding about how these processes are regulated. Here, we identify WDR31 as a new ciliary protein, and analysis from zebrafish andCaenorhabditis elegansreveals the role ofWDR31in regulating the cilia morphology. We find that loss of WDR-31 together with RP-2 and ELMD-1 (the sole ortholog ELMOD1-3) results in ciliary accumulations of IFT Complex B components and KIF17 kinesin, with fewer IFT/BBSome particles traveling along cilia in both anterograde and retrograde directions, suggesting that the IFT/BBSome entry into the cilia and exit from the cilia are impacted. Furthermore, anterograde IFT in the middle segment travels at increased speed inwdr-31;rpi-2;elmd-1. Remarkably, a non-ciliary protein leaks into the cilia ofwdr-31;rpi-2;elmd-1, possibly because of IFT defects. This work reveals WDR31–RP-2–ELMD-1 as IFT and BBSome trafficking regulators.
50
Lucaciu, Laura A., Radu Seicean, Alina Uifălean, Maria Iacobescu, Cristina A. Iuga e Andrada Seicean. "Unveiling Distinct Proteomic Signatures in Complicated Crohn’s Disease That Could Predict the Disease Course". International Journal of Molecular Sciences 24, n. 23 (30 novembre 2023): 16966. http://dx.doi.org/10.3390/ijms242316966.
Abstract (sommario):
Crohn’s disease (CD) is characterized by a chronic, progressive inflammation of the gastrointestinal tract often leading to complications, such as strictures and fistulae. Currently, there are no validated tools anticipating short- and long-term outcomes at an early stage. This investigation aims to elucidate variations in protein abundance across distinct CD phenotypes with the objective of uncovering potential biomarkers implicated in disease advancement. Serum samples collected from 30 CD patients and 15 healthy age-matched controls (HC) were subjected to depletion of highly abundant proteins and to a label-free mass spectrometry analysis. Twenty-four proteins were shown to be significantly different when comparing CD with HC. Of these, WD repeat-containing protein 31 (WDR31), and proteins involved in the acute inflammatory response, leucine-rich alpha-2-glycoprotein (LRG1) and serum amyloid A1 (SAA1), were more abundant in the aggressive subgroup. Against standard biomarkers, a positive correlation between SAA1 and WDR31 and C-reactive protein (CRP) was found. In this study, a unique serum biomarker panel for aggressive CD was identified, which could aid in predicting the disease course.