The Experts below are selected from a list of 531 Experts worldwide ranked by ideXlab platform
Chengyu Liang - One of the best experts on this subject based on the ideXlab platform.
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UVRAG in autophagy inflammation and cancer
Autophagy, 2020Co-Authors: Ying Song, Christine Quach, Chengyu LiangAbstract:Macroautophagy/autophagy deregulation has been observed in perpetuated inflammation and the proliferation of tumor cells. However, the mechanisms underlying these changes have yet to be well-identified. UVRAG is one of the key players of autophagy, but its role in vivo remained puzzling. Our recent study utilized a mouse model with inducible expression of a cancer-derived frameshift (FS) mutation in UVRAG that dominant-negatively inhibits wild-type UVRAG, resulting in impaired stimulus-induced autophagy. The systemically compromised autophagy, particularly mitophagy, notably increases inflammation and associated pathologies. Furthermore, our discovery indicates that time-dependent autophagy suppression and ensuing CTNNB1/β-catenin activation may serve as one tumor-promoting mechanism underpinning age-related cancer susceptibility.
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darkening with UVRAG
Autophagy, 2019Co-Authors: Gyubeom Jang, Christine Quach, Chengyu LiangAbstract:Ultraviolet radiation (UVR)-induced skin pigmentation, afforded by the dark organelles termed melanosomes, accounts for the first-line protection against environmental UVR that increases the risk of developing skin cancers including melanoma. We have recently discovered that UVRAG, originally identified as a BECN1-binding macroautophagy/autophagy protein, appears to have a specialized function in melanosome biogenesis beyond autophagy through its interaction with the biogenesis of lysosome-related organelles complex 1 (BLOC-1). This melanogenic function of UVRAG is controlled by the melanocyte-specific transcription factor MITF as a downstream effector of the α-melanocyte-stimulating hormone (α-MSH)-cAMP signaling in the suntan response, which is compromised in BRAF mutant melanoma. Thus we propose a new mode of UVRAG activity and regulation in melanocyte biology that may affect melanoma predisposition.
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central role of autophagic UVRAG in melanogenesis and the suntan response
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Yongfei Yang, Qiaoxiu Wang, Christine Quach, Gyubeom Jang, Xuanjun Yang, Shihui Zhao, Zengqiang Yuan, Hyera Lee, Hanbing Zhong, Chengyu LiangAbstract:UV-induced cell pigmentation represents an important mechanism against skin cancers. Sun-exposed skin secretes α-MSH, which induces the lineage-specific transcriptional factor MITF and activates melanogenesis in melanocytes. Here, we show that the autophagic tumor suppressor UVRAG plays an integral role in melanogenesis by interaction with the biogenesis of lysosome-related organelles complex 1 (BLOC-1). This interaction is required for BLOC-1 stability and for BLOC-1-mediated cargo sorting and delivery to melanosomes. Absence of UVRAG dispersed BLOC-1 distribution and activity, resulting in impaired melanogenesis in vitro and defective melanocyte development in zebrafish in vivo. Furthermore, our results establish UVRAG as an important effector for melanocytes' response to α-MSH signaling as a direct target of MITF and reveal the molecular basis underlying the association between oncogenic BRAF and compromised UV protection in melanoma.
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frameshift mutation of UVRAG switching a tumor suppressor to an oncogene in colorectal cancer
Autophagy, 2015Co-Authors: Chengyu LiangAbstract:Colorectal cancer (CRC) ranks as the second leading cause of cancer-related deaths in the Western world. It has a nearly 50% metastasis rate and only a subset of patients respond to current treatment strategy. UVRAG, a key autophagy effector and a guardian of chromosomal stability, is truncated by a frameshift (FS) mutation in CRC with microsatellite instability (MSI). However, the pathological and clinical significance of this UVRAG truncation remains less understood. Our recent study discovered that this FS mutation yields a much shortened form of the UVRAG protein, which counteracts most of the tumor-suppressor functions of wild-type (WT) UVRAG in autophagy, centrosome stability, and DNA repair in a dominant-negative fashion. Whereas this truncated mutation of UVRAG promotes tumorigenesis, epithelial-to-mesenchymal transition, and metastasis, it appears to sensitize CRC tumors to adjuvant chemotherapy, making it a potential molecular marker to individualize therapeutic approach in CRC.
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UVRAG is required for virus entry through combinatorial interaction with the class c vps complex and snares
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Sara Dolatshahi Pirooz, Tian Zhang, Zhen Zhao, Douglas Oconnell, Xiaowei Zhang, Payam Khalilzadeh, Samad Aminibavilolyaee, Michael Farzan, Chengyu LiangAbstract:Enveloped viruses exploit the endomembrane system to enter host cells. Through a cascade of membrane-trafficking events, virus-bearing vesicles fuse with acidic endosomes and/or lysosomes mediated by SNAREs triggering viral fusion. However, the molecular mechanisms underlying this process remain elusive. Here, we found that UV-radiation resistance-associated gene (UVRAG), an autophagic tumor suppressor, is required for the entry of the prototypic negative-strand RNA virus, including influenza A virus and vesicular stomatitis virus, by a mechanism independent of IFN and autophagy. UVRAG mediates viral endocytic transport and membrane penetration through interactions with the class C vacuolar protein sorting (C-Vps) tethering complex and endosomal glutamine-containing SNAREs [syntaxin 7 (STX7), STX8, and vesicle transport through t-SNARE homolog 1B (Vti1b)], leading to the assembly of a fusogenic trans-SNARE complex involving vesicle-associated membrane protein (VAMP8), but not VAMP7. Indeed, UVRAG stimulates VAMP8 translocation to virus-bearing endosomes. Inhibition of VAMP8, but not VAMP7, significantly reduces viral entry. Our data indicate that UVRAG, in concert with C-Vps, regulates viral entry by assembling a specific fusogenic SNARE complex. Thus, UVRAG governs downstream viral entry, highlighting an important pathway capable of potential antiviral therapeutics.
Yanxiang Zhao - One of the best experts on this subject based on the ideXlab platform.
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targeting the potent beclin 1 UVRAG coiled coil interaction with designed peptides enhances autophagy and endolysosomal trafficking
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Xianxiu Qiu, Zhenyu Yue, Wenchao Yang, Wenchao Liu, Hanming Shen, Renxiao Wang, Yanxiang ZhaoAbstract:The Beclin 1–Vps34 complex, known as “mammalian class III PI3K,” plays essential roles in membrane-mediated transport processes including autophagy and endosomal trafficking. Beclin 1 acts as a scaffolding molecule for the complex and readily transits from its metastable homodimeric state to interact with key modulators such as Atg14L or UVRAG and form functionally distinct Atg14L/UVRAG-containing Beclin 1–Vps34 subcomplexes. The Beclin 1–Atg14L/UVRAG interaction relies critically on their coiled-coil domains, but the molecular mechanism remains poorly understood. We determined the crystal structure of Beclin 1–UVRAG coiled-coil complex and identified a strengthened interface with both hydrophobic pairings and electrostatically complementary interactions. This structure explains why the Beclin 1–UVRAG interaction is more potent than the metastable Beclin 1 homodimer. Potent Beclin 1–UVRAG interaction is functionally significant because it renders UVRAG more competitive than Atg14L in Beclin 1 binding and is critical for promoting endolysosomal trafficking. UVRAG coiled-coil mutants with weakened Beclin 1 binding do not outcompete Atg14L and fail to promote endolysosomal degradation of the EGF receptor (EGFR). We designed all-hydrocarbon stapled peptides that specifically targeted the C-terminal part of the Beclin 1 coiled-coil domain to interfere with its homodimerization. One such peptide reduced Beclin 1 self-association, promoted Beclin 1–Atg14L/UVRAG interaction, increased autophagic flux, and enhanced EGFR degradation. Our results demonstrate that the targeting Beclin 1 coiled-coil domain with designed peptides to induce the redistribution of Beclin 1 among its self-associated form or Atg14L/UVRAG-containing complexes enhances both autophagy and endolysosomal trafficking.
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ARTICLE
2016Co-Authors: Zhenyu Yue, Yanxiang ZhaoAbstract:Beclin 1 is a core component of the Class III Phosphatidylinositol 3-Kinase VPS34 complex. The coiled coil domain of Beclin 1 serves as an interaction platform for assembly of distinct Atg14L- and UVRAG-containing complexes to modulate VPS34 activity. Here we report the crystal structure of the coiled coil domain that forms an antiparallel dimer and is rendered metastable by a series of ‘ imperfect ’ a- d ’ pairings at its coiled coil interface. Atg14L and UVRAG promote the transition of metastable homodimeric Beclin 1 to heterodimeric Beclin1-Atg14L / UVRAG assembly. Beclin 1 mutants with their ‘ imperfect ’ a- d ’ pairings modifi ed to enhance self-interaction, show distinctively altered interactions with Atg14L or UVRAG. These results suggest that specifi c utilization of the dimer interface and modulation of the homodimer – heterodimer transition by Beclin 1-interacting partners may underlie the molecular mechanism that controls the formation of various Beclin1 – VPS34 subcomplexes to exert their effect on an array of VPS34-related activities, including autophagy
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Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex
PLoS genetics, 2014Co-Authors: Nicole C. Mcknight, Nathaniel Heintz, Yanxiang Zhao, Yun Zhong, Mitchell S. Wold, Shiaoching Gong, Greg R. Phillips, Zhixun Dou, Wei-xing Zong, Zhenyu YueAbstract:Deficiency of autophagy protein beclin 1 is implicated in tumorigenesis and neurodegenerative diseases, but the molecular mechanism remains elusive. Previous studies showed that Beclin 1 coordinates the assembly of multiple VPS34 complexes whose distinct phosphatidylinositol 3-kinase III (PI3K-III) lipid kinase activities regulate autophagy at different steps. Recent evidence suggests a function of beclin 1 in regulating multiple VPS34-mediated trafficking pathways beyond autophagy; however, the precise role of beclin 1 in autophagy-independent cellular functions remains poorly understood. Herein we report that beclin 1 regulates endocytosis, in addition to autophagy, and is required for neuron viability in vivo. We find that neuronal beclin 1 associates with endosomes and regulates EEA1/early endosome localization and late endosome formation. Beclin 1 maintains proper cellular phosphatidylinositol 3-phosphate (PI(3)P) distribution and total levels, and loss of beclin 1 causes a disruption of active Rab5 GTPase-associated endosome formation and impairment of endosome maturation, likely due to a failure of Rab5 to recruit VPS34. Furthermore, we find that Beclin 1 deficiency causes complete loss of the UVRAG-VPS34 complex and associated lipid kinase activity. Interestingly, beclin 1 deficiency impairs p40phox-linked endosome formation, which is rescued by overexpressed UVRAG or beclin 1, but not by a coiled-coil domain-truncated beclin 1 (a UVRAG-binding mutant), Atg14L or RUBICON. Thus, our study reveals the essential role for beclin 1 in neuron survival involving multiple membrane trafficking pathways including endocytosis and autophagy, and suggests that the UVRAG-beclin 1 interaction underlies beclin 1's function in endocytosis.
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the becn1 coiled coil domain an imperfect homodimer interface that facilitates atg14 and UVRAG binding
Autophagy, 2012Co-Authors: Mingjie Zhang, Zhenyu Yue, Yanxiang ZhaoAbstract:The coiled-coil domain of BECN1 serves as a protein interaction platform to recruit two major autophagy regulators ATG14 and UVRAG. Our crystal structure of the BECN1 coiled-coil domain reveals a homodimer with an imperfect dimer interface. This “imperfect” feature favors the formation of a stable BECN1-ATG14 or BECN1-UVRAG heterodimer over a metastable BECN1 homodimer to promote autophagy and/or endocytic pathways.
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imperfect interface of beclin1 coiled coil domain regulates homodimer and heterodimer formation with atg14l and UVRAG
Nature Communications, 2012Co-Authors: Xiaohua Li, Mingjie Zhang, Liqiang He, Sarah F Funderburk, Yanxiang ZhaoAbstract:Beclin1 is a key regulator of VPS34-related processes, including autophagy. Li et al. solve the crystal structure of Beclin 1 CC domain, an antiparallel dimer that is rendered metastable by a series of a-d' pairings, which determines its ability to form distinct heterodimers either with Atg14L or UVRAG.
Jae U Jung - One of the best experts on this subject based on the ideXlab platform.
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UVRAG is required for organ rotation by regulating notch endocytosis in drosophila
Developmental Biology, 2011Co-Authors: Gina Lee, Chengyu Liang, Jae U Jung, Gihyun Park, Cholsoon Jang, Jongkyeong ChungAbstract:Heterotaxy characterized by abnormal left–right body asymmetry causes diverse congenital anomalies. Organ rotation is a crucial developmental process to establish the left–right patterning during animal development. However, the molecular basis of how organ rotation is regulated is poorly understood. Here we report that Drosophila UV-resistance associated gene (UVRAG), a tumor suppressor that regulates autophagy and endocytosis, plays unexpected roles in controlling organ rotation. Loss-of-function mutants of UVRAG show seriously impaired organ rotation phenotypes, which are associated with defects in endocytic trafficking rather than autophagy. Blunted endocytic degradation by UVRAG deficiency causes endosomal accumulation of Notch, resulting in abnormally enhanced Notch activity. Knockdown of Notch itself or expression of a dominant negative form of Notch transcriptional co-activator Mastermind is sufficient to rescue the rotation defect in UVRAG mutants. Consistently, UVRAG-mutated heterotaxy patient cells also display highly increased Notch protein levels. These results suggest evolutionarily conserved roles of UVRAG in organ rotation by regulating Notch endocytic degradation.
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beyond autophagy the role of UVRAG in membrane trafficking
Autophagy, 2008Co-Authors: Chengyu Liang, Donna Sir, Steven Lee, Jae U JungAbstract:Autophagy is a lysosome-directed membrane trafficking event for the degradation of cytoplasmic components, including organelles. The past few years have seen a great advance in our understanding of the cellular machinery of autophagosome biogenesis, the hallmark of autophagy. However, our global understanding of autophagosome maturity remains relatively poor and fragmented. The topological similarity of autophagosome and endosome delivery to lysosomes suggests that autophagic and endosomal maturation may have evolved to share associated machinery to promote the lysosomal delivery of their cargoes. We have recently discovered that UVRAG, originally identified as a Beclin 1-binding autophagy protein, appears to be an important factor in autophagic and endosomal trafficking through its interaction with the class C Vps tethering complex. Given the ability of UVRAG to bind Beclin 1 and the class C Vps complex in a genetically and functionally separable manner, it may serve as an important regulator for the spatial and/or temporal control of diverse cellular trafficking events. As more non-autophagic functions of UVRAG are unveiled, our understanding of seemingly different cellular processes may move a step further.
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bif 1 interacts with beclin 1 through UVRAG and regulates autophagy and tumorigenesis
Nature Cell Biology, 2007Co-Authors: Yoshinori Takahashi, Chengyu Liang, Jae U Jung, Mei Sun, Jin Q Cheng, Domenico Coppola, Norimasa Matsushita, Hernani D Cualing, Yuya Sato, James J MuleAbstract:Autophagy is an evolutionarily conserved ‘self-eating’ process. Although the genes essential for autophagy (named Atg) have been identified in yeast, the molecular mechanism of how Atg proteins control autophagosome formation in mammalian cells remains to be elucidated. Here, we demonstrate that Bif-1 (also known as Endophilin B1) interacts with Beclin 1 through ultraviolet irradiation resistance-associated gene (UVRAG) and functions as a positive mediator of the class III PI(3) kinase (PI(3)KC3). In response to nutrient deprivation, Bif-1 localizes to autophagosomes where it colocalizes with Atg5, as well as microtubule-associated protein light chain 3 (LC3). Furthermore, loss of Bif-1 suppresses autophagosome formation. Although the SH3 domain of Bif-1 is sufficient for binding to UVRAG, both the BAR and SH3 domains are required for Bif-1 to activate PI(3)KC3 and induce autophagosome formation. We also observed that Bif-1 ablation prolongs cell survival under starvation conditions. Moreover, knockout of Bif-1 significantly enhances the
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UVRAG a new player in autophagy and tumor cell growth
Autophagy, 2007Co-Authors: Chengyu Liang, Pinghui Feng, Jae U JungAbstract:Autophagy has a well-documented role in the maintenance of homeostasis and the response to stressful environments and it is often deregulated in various human diseases including cancer. The regulation of the Beclin 1-PI3KC3 complex lipid kinase activity is a critical element in the autophagy signaling pathway. Previous studies1 have demonstrated that Beclin 1-PI3KC3-mediated autophagy is negatively regulated by a proto-oncogene Bcl-2. We have recently identified a novel coiled-coil UVRAG tumor suppressor candidate, which positively engages in Beclin 1-dependent autophagy. UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis. This finding adds a new player to the emerging picture of the autophagy network, underscoring the importance of the coordinated activity between Bcl-2 and UVRAG in the regulation of Beclin 1-PI3KC3- mediated autophagy and tumor cell control.Addendum to:Autophagic and Tumor Suppressor Activity of a Novel Beclin 1-Binding Protein UVRA...
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Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG
Nature Cell Biology, 2006Co-Authors: Chengyu Liang, Pinghui Feng, Iris Dotan, Dan Canaani, Jae U JungAbstract:Autophagy, the degradation of cytoplasmic components, is an evolutionarily conserved homeostatic process involved in environmental adaptation, lifespan determination and tumour development. The tumor suppressor Beclin1 is part of the PI(3) kinase class III (PI(3)KC3) lipid-kinase complex that induces autophagy. The autophagic activity of the Beclin1–PI(3)KC3 complex, however, is suppressed by Bcl-2. Here, we report the identification of a novel coiled–coil UV irradiation resistance-associated gene (UVRAG) as a positive regulator of the Beclin1–PI(3)KC3 complex. UVRAG, a tumour suppressor candidate that is monoallelically mutated at high frequency in human colon cancers, associates with the Beclin1–Bcl-2–PI(3)KC3 multiprotein complex, where UVRAG and Beclin1 interdependently induce autophagy. UVRAG-mediated activation of the Beclin1–PI(3)KC3 complex promotes autophagy and also suppresses the proliferation and tumorigenicity of human colon cancer cells. These results identify UVRAG as an essential component of the Beclin1–PI(3)KC3 lipid kinase complex that is an important signalling checkpoint for autophagy and tumour-cell growth.
Zhenyu Yue - One of the best experts on this subject based on the ideXlab platform.
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targeting the potent beclin 1 UVRAG coiled coil interaction with designed peptides enhances autophagy and endolysosomal trafficking
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Xianxiu Qiu, Zhenyu Yue, Wenchao Yang, Wenchao Liu, Hanming Shen, Renxiao Wang, Yanxiang ZhaoAbstract:The Beclin 1–Vps34 complex, known as “mammalian class III PI3K,” plays essential roles in membrane-mediated transport processes including autophagy and endosomal trafficking. Beclin 1 acts as a scaffolding molecule for the complex and readily transits from its metastable homodimeric state to interact with key modulators such as Atg14L or UVRAG and form functionally distinct Atg14L/UVRAG-containing Beclin 1–Vps34 subcomplexes. The Beclin 1–Atg14L/UVRAG interaction relies critically on their coiled-coil domains, but the molecular mechanism remains poorly understood. We determined the crystal structure of Beclin 1–UVRAG coiled-coil complex and identified a strengthened interface with both hydrophobic pairings and electrostatically complementary interactions. This structure explains why the Beclin 1–UVRAG interaction is more potent than the metastable Beclin 1 homodimer. Potent Beclin 1–UVRAG interaction is functionally significant because it renders UVRAG more competitive than Atg14L in Beclin 1 binding and is critical for promoting endolysosomal trafficking. UVRAG coiled-coil mutants with weakened Beclin 1 binding do not outcompete Atg14L and fail to promote endolysosomal degradation of the EGF receptor (EGFR). We designed all-hydrocarbon stapled peptides that specifically targeted the C-terminal part of the Beclin 1 coiled-coil domain to interfere with its homodimerization. One such peptide reduced Beclin 1 self-association, promoted Beclin 1–Atg14L/UVRAG interaction, increased autophagic flux, and enhanced EGFR degradation. Our results demonstrate that the targeting Beclin 1 coiled-coil domain with designed peptides to induce the redistribution of Beclin 1 among its self-associated form or Atg14L/UVRAG-containing complexes enhances both autophagy and endolysosomal trafficking.
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ARTICLE
2016Co-Authors: Zhenyu Yue, Yanxiang ZhaoAbstract:Beclin 1 is a core component of the Class III Phosphatidylinositol 3-Kinase VPS34 complex. The coiled coil domain of Beclin 1 serves as an interaction platform for assembly of distinct Atg14L- and UVRAG-containing complexes to modulate VPS34 activity. Here we report the crystal structure of the coiled coil domain that forms an antiparallel dimer and is rendered metastable by a series of ‘ imperfect ’ a- d ’ pairings at its coiled coil interface. Atg14L and UVRAG promote the transition of metastable homodimeric Beclin 1 to heterodimeric Beclin1-Atg14L / UVRAG assembly. Beclin 1 mutants with their ‘ imperfect ’ a- d ’ pairings modifi ed to enhance self-interaction, show distinctively altered interactions with Atg14L or UVRAG. These results suggest that specifi c utilization of the dimer interface and modulation of the homodimer – heterodimer transition by Beclin 1-interacting partners may underlie the molecular mechanism that controls the formation of various Beclin1 – VPS34 subcomplexes to exert their effect on an array of VPS34-related activities, including autophagy
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Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex
PLoS genetics, 2014Co-Authors: Nicole C. Mcknight, Nathaniel Heintz, Yanxiang Zhao, Yun Zhong, Mitchell S. Wold, Shiaoching Gong, Greg R. Phillips, Zhixun Dou, Wei-xing Zong, Zhenyu YueAbstract:Deficiency of autophagy protein beclin 1 is implicated in tumorigenesis and neurodegenerative diseases, but the molecular mechanism remains elusive. Previous studies showed that Beclin 1 coordinates the assembly of multiple VPS34 complexes whose distinct phosphatidylinositol 3-kinase III (PI3K-III) lipid kinase activities regulate autophagy at different steps. Recent evidence suggests a function of beclin 1 in regulating multiple VPS34-mediated trafficking pathways beyond autophagy; however, the precise role of beclin 1 in autophagy-independent cellular functions remains poorly understood. Herein we report that beclin 1 regulates endocytosis, in addition to autophagy, and is required for neuron viability in vivo. We find that neuronal beclin 1 associates with endosomes and regulates EEA1/early endosome localization and late endosome formation. Beclin 1 maintains proper cellular phosphatidylinositol 3-phosphate (PI(3)P) distribution and total levels, and loss of beclin 1 causes a disruption of active Rab5 GTPase-associated endosome formation and impairment of endosome maturation, likely due to a failure of Rab5 to recruit VPS34. Furthermore, we find that Beclin 1 deficiency causes complete loss of the UVRAG-VPS34 complex and associated lipid kinase activity. Interestingly, beclin 1 deficiency impairs p40phox-linked endosome formation, which is rescued by overexpressed UVRAG or beclin 1, but not by a coiled-coil domain-truncated beclin 1 (a UVRAG-binding mutant), Atg14L or RUBICON. Thus, our study reveals the essential role for beclin 1 in neuron survival involving multiple membrane trafficking pathways including endocytosis and autophagy, and suggests that the UVRAG-beclin 1 interaction underlies beclin 1's function in endocytosis.
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the becn1 coiled coil domain an imperfect homodimer interface that facilitates atg14 and UVRAG binding
Autophagy, 2012Co-Authors: Mingjie Zhang, Zhenyu Yue, Yanxiang ZhaoAbstract:The coiled-coil domain of BECN1 serves as a protein interaction platform to recruit two major autophagy regulators ATG14 and UVRAG. Our crystal structure of the BECN1 coiled-coil domain reveals a homodimer with an imperfect dimer interface. This “imperfect” feature favors the formation of a stable BECN1-ATG14 or BECN1-UVRAG heterodimer over a metastable BECN1 homodimer to promote autophagy and/or endocytic pathways.
Sara Dolatshahi Pirooz - One of the best experts on this subject based on the ideXlab platform.
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Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4(DDB2) E3 Ligase.
Molecular cell, 2016Co-Authors: Yongfei Yang, Qiaoxiu Wang, Mi Jeong Kwak, Sally B Chen, Douglas O'connell, Tian Zhang, Sara Dolatshahi Pirooz, Yong Heui JeonAbstract:UV-induced DNA damage, a major risk factor for skin cancers, is primarily repaired by nucleotide excision repair (NER). UV radiation resistance-associated gene (UVRAG) is a tumor suppressor involved in autophagy. It was initially isolated as a cDNA partially complementing UV sensitivity in xeroderma pigmentosum (XP), but this was not explored further. Here we show that UVRAG plays an integral role in UV-induced DNA damage repair. It localizes to photolesions and associates with DDB1 to promote the assembly and activity of the DDB2-DDB1-Cul4A-Roc1 (CRL4(DDB2)) ubiquitin ligase complex, leading to efficient XPC recruitment and global genomic NER. UVRAG depletion decreased substrate handover to XPC and conferred UV-damage hypersensitivity. We confirmed the importance of UVRAG for UV-damage tolerance using a Drosophila model. Furthermore, increased UV-signature mutations in melanoma correlate with reduced expression of UVRAG. Our results identify UVRAG as a regulator of CRL4(DDB2)-mediated NER and suggest that its expression levels may influence melanoma predisposition.
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truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers
Nature Communications, 2015Co-Authors: Zhen Zhao, Yongfei Yang, Tian Zhang, Sara Dolatshahi Pirooz, Douglas Oconnell, Xiaowei Zhang, Joohyung Lee, Bino Varghese, Janae Yip, Yong ZhangAbstract:Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAG(FS) in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAG(FS) abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAG(FS) can trigger CRC metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. Interestingly, UVRAG(FS) expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. These results identify UVRAG as a new MSI target gene and provide a mechanism for UVRAG participation in CRC pathogenesis and treatment response.
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UVRAG is required for virus entry through combinatorial interaction with the class c vps complex and snares
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Sara Dolatshahi Pirooz, Tian Zhang, Zhen Zhao, Douglas Oconnell, Xiaowei Zhang, Payam Khalilzadeh, Samad Aminibavilolyaee, Michael Farzan, Chengyu LiangAbstract:Enveloped viruses exploit the endomembrane system to enter host cells. Through a cascade of membrane-trafficking events, virus-bearing vesicles fuse with acidic endosomes and/or lysosomes mediated by SNAREs triggering viral fusion. However, the molecular mechanisms underlying this process remain elusive. Here, we found that UV-radiation resistance-associated gene (UVRAG), an autophagic tumor suppressor, is required for the entry of the prototypic negative-strand RNA virus, including influenza A virus and vesicular stomatitis virus, by a mechanism independent of IFN and autophagy. UVRAG mediates viral endocytic transport and membrane penetration through interactions with the class C vacuolar protein sorting (C-Vps) tethering complex and endosomal glutamine-containing SNAREs [syntaxin 7 (STX7), STX8, and vesicle transport through t-SNARE homolog 1B (Vti1b)], leading to the assembly of a fusogenic trans-SNARE complex involving vesicle-associated membrane protein (VAMP8), but not VAMP7. Indeed, UVRAG stimulates VAMP8 translocation to virus-bearing endosomes. Inhibition of VAMP8, but not VAMP7, significantly reduces viral entry. Our data indicate that UVRAG, in concert with C-Vps, regulates viral entry by assembling a specific fusogenic SNARE complex. Thus, UVRAG governs downstream viral entry, highlighting an important pathway capable of potential antiviral therapeutics.
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ptdins 3 p bound UVRAG coordinates golgi er retrograde and atg9 transport by differential interactions with the er tether and the beclin 1 complex
Nature Cell Biology, 2013Co-Authors: Joohyung Lee, Tian Zhang, Sara Dolatshahi Pirooz, Zhen Zhao, Irene Ghozalli, Nagakumar Bharatham, Wenhwa Lee, Yoshinori Takahashi, Honggang Wang, Arlet MinassianAbstract:Endoplasmic reticulum (ER)-Golgi membrane transport and autophagy are intersecting trafficking pathways that are tightly regulated and crucial for homeostasis, development and disease. Here, we identify UVRAG, a beclin-1-binding autophagic factor, as a phosphatidylinositol-3-phosphate (PtdIns(3)P)-binding protein that depends on PtdIns(3)P for its ER localization. We further show that UVRAG interacts with RINT-1, and acts as an integral component of the RINT-1-containing ER tethering complex, which couples phosphoinositide metabolism to COPI-vesicle tethering. Displacement or knockdown of UVRAG profoundly disrupted COPI cargo transfer to the ER and Golgi integrity. Intriguingly, autophagy caused the dissociation of UVRAG from the ER tether, which in turn worked in concert with the Bif-1-beclin-1-PI(3)KC3 complex to mobilize Atg9 translocation for autophagosome formation. These findings identify a regulatory mechanism that coordinates Golgi-ER retrograde and autophagy-related vesicular trafficking events through physical and functional interactions between UVRAG, phosphoinositide and their regulatory factors, thereby ensuring spatiotemporal fidelity of membrane trafficking and maintenance of organelle homeostasis.
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UVRAG at the crossroad of autophagy and genomic stability
Autophagy, 2012Co-Authors: Zhen Zhao, Sara Dolatshahi Pirooz, Irene Ghozalli, Chengyu LiangAbstract:UVRAG is a promoter of the autophagy pathway, and its deficiency may fuel the development of cancers. Intriguingly, our recent study has demonstrated that this protein also mediates the repair of damaged DNA and patrols centrosome stability, mechanisms that commonly prevent cancer progression, in a manner independent of its role in autophagy signaling. Given the central role of UVRAG in genomic stability and autophagic cleaning, it is speculated that UVRAG is a bona fide genome protector and that the decrease in UVRAG seen in some cancers may render these cells vulnerable to chromosomal damage, making UVRAG an appealing target for cancer therapy.
