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Bo Wang - One of the best experts on this subject based on the ideXlab platform.
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ULK1 and ulk2 regulate stress granule disassembly through phosphorylation and activation of vcp p97
Molecular Cell, 2019Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Amber L Ward, Honghu Quan, Ashutosh Mishra, Sadie Miki SakuradaAbstract:Summary Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43–positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP’s activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in ULK1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
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ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97
Molecular Cell, 2019Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Amber L Ward, Honghu Quan, Ashutosh Mishra, Sadie Miki SakuradaAbstract:Summary Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43–positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP’s activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in ULK1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
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the autophagy inducing kinases ULK1 and ulk2 regulate axon guidance in the developing mouse forebrain via a noncanonical pathway
Autophagy, 2018Co-Authors: Bo Wang, Rekha Iyengar, Xiujie Liharms, Alfonso Lavado, Linda Horner, Sharon Frase, Christopher Wright, Mao Yang, Junlin Guan, Douglas R GreenAbstract:Mammalian ULK1 (unc-51 like kinase 1) and ULK2, Caenorhabditis elegans UNC-51, and Drosophila melanogaster Atg1 are serine/threonine kinases that regulate flux through the autophagy pathway in response to various types of cellular stress. C. elegans UNC-51 and D. melanogaster Atg1 also promote axonal growth and defasciculation; disruption of these genes results in defective axon guidance in invertebrates. Although disrupting ULK1/2 function impairs normal neurite outgrowth in vitro, the role of ULK1 and ULK2 in the developing brain remains poorly characterized. Here, we show that ULK1 and ULK2 are required for proper projection of axons in the forebrain. Mice lacking ULK1 and Ulk2 in their central nervous systems showed defects in axonal pathfinding and defasciculation affecting the corpus callosum, anterior commissure, corticothalamic axons and thalamocortical axons. These defects impaired the midline crossing of callosal axons and caused hypoplasia of the anterior commissure and disorganization of the somatosensory cortex. The axon guidance defects observed in ULK1/2 double-knockout mice and central nervous system-specific (Nes-Cre) ULK1/2-conditional double-knockout mice were not recapitulated in mice lacking other autophagy genes (i.e., Atg7 or Rb1cc1 [RB1-inducible coiled-coil 1]). The brains of ULK1/2-deficient mice did not show stem cell defects previously attributed to defective autophagy in ambra1 (autophagy/Beclin 1 regulator 1)- and Rb1cc1-deficient mice or accumulation of SQSTM1 (sequestosome 1)+ or ubiquitin+ deposits. Together, these data demonstrate that ULK1 and ULK2 regulate axon guidance during mammalian brain development via a noncanonical (i.e., autophagy-independent) pathway.
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The autophagy-inducing kinases, ULK1 and ULK2, regulate axon guidance in the developing mouse forebrain via a noncanonical pathway.
Autophagy, 2017Co-Authors: Bo Wang, Rekha Iyengar, Xiu Jie Li-harms, Alfonso Lavado, Linda Horner, Christopher Wright, Mao Yang, Junlin Guan, Sharon FraseAbstract:ABSTRACTMammalian ULK1 (unc-51 like kinase 1) and ULK2, Caenorhabditis elegans UNC-51, and Drosophila melanogaster Atg1 are serine/threonine kinases that regulate flux through the autophagy pathway...
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Canonical and noncanonical functions of ULK/Atg1
Current Opinion in Cell Biology, 2017Co-Authors: Bo Wang, Mondira KunduAbstract:Mammalian Unc-51-like kinases 1 and 2 (ULK1 and ULK2) belong to the ULK/Atg1 family of serine/threonine kinases, which are conserved from yeast to mammals. Although ULK/Atg1 is best known for regulating flux through the autophagy pathway, it has evolutionarily conserved noncanonical functions in protein trafficking that are essential for maintaining cellular homeostasis. As a direct target of energy- and nutrient-sensing kinases, ULK/Atg1 is positioned to regulate the distribution and use of cellular resources in response to metabolic cues. In this review, we provide an overview of the molecular mechanisms through which ULK/Atg1 carries out its canonical and noncanonical functions and the signaling pathways that link its function to metabolism. We also highlight potential contributions of ULK/Atg1 in human diseases, including cancer and neurodegeneration.
Sadie Miki Sakurada - One of the best experts on this subject based on the ideXlab platform.
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ULK1 and ulk2 regulate stress granule disassembly through phosphorylation and activation of vcp p97
Molecular Cell, 2019Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Amber L Ward, Honghu Quan, Ashutosh Mishra, Sadie Miki SakuradaAbstract:Summary Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43–positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP’s activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in ULK1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
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ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97
Molecular Cell, 2019Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Amber L Ward, Honghu Quan, Ashutosh Mishra, Sadie Miki SakuradaAbstract:Summary Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43–positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP’s activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in ULK1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
Timothy I. Shaw - One of the best experts on this subject based on the ideXlab platform.
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ULK1 and ulk2 regulate stress granule disassembly through phosphorylation and activation of vcp p97
Molecular Cell, 2019Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Amber L Ward, Honghu Quan, Ashutosh Mishra, Sadie Miki SakuradaAbstract:Summary Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43–positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP’s activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in ULK1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
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ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97
Molecular Cell, 2019Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Amber L Ward, Honghu Quan, Ashutosh Mishra, Sadie Miki SakuradaAbstract:Summary Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43–positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP’s activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in ULK1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
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The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis
Molecular Cell, 2016Co-Authors: Bo Wang, E.b. Frankel, Rekha Iyengar, Xiu Jie Li-harms, Timothy I. Shaw, Christopher Wright, Liang Ge, Lu Xu, Tullia LindstenAbstract:Summary ULK1 and ULK2 are thought to be essential for initiating autophagy, and ULK1/2 -deficient mice die perinatally of autophagy-related defects. Therefore, we used a conditional knockout approach to investigate the roles of ULK1/2 in the brain. Although the mice showed neuronal degeneration, the neurons showed no accumulation of P62 + /ubiquitin + inclusions or abnormal membranous structures, which are observed in mice lacking other autophagy genes. Rather, neuronal death was associated with activation of the unfolded protein response (UPR) pathway. An unbiased proteomics approach identified SEC16A as an ULK1/2 interaction partner. ULK-mediated phosphorylation of SEC16A regulated the assembly of endoplasmic reticulum (ER) exit sites and ER-to-Golgi trafficking of specific cargo, and did not require other autophagy proteins (e.g., ATG13). The defect in ER-to-Golgi trafficking activated the UPR pathway in ULK-deficient cells; both processes were reversed upon expression of SEC16A with a phosphomimetic substitution. Thus, the regulation of ER-to-Golgi trafficking by ULK1/2 is essential for cellular homeostasis.
James Messing - One of the best experts on this subject based on the ideXlab platform.
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ULK1 and ulk2 regulate stress granule disassembly through phosphorylation and activation of vcp p97
Molecular Cell, 2019Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Amber L Ward, Honghu Quan, Ashutosh Mishra, Sadie Miki SakuradaAbstract:Summary Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43–positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP’s activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in ULK1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
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ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97
Molecular Cell, 2019Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Amber L Ward, Honghu Quan, Ashutosh Mishra, Sadie Miki SakuradaAbstract:Summary Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43–positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP’s activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in ULK1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
Mondira Kundu - One of the best experts on this subject based on the ideXlab platform.
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Canonical and noncanonical functions of ULK/Atg1
Current Opinion in Cell Biology, 2017Co-Authors: Bo Wang, Mondira KunduAbstract:Mammalian Unc-51-like kinases 1 and 2 (ULK1 and ULK2) belong to the ULK/Atg1 family of serine/threonine kinases, which are conserved from yeast to mammals. Although ULK/Atg1 is best known for regulating flux through the autophagy pathway, it has evolutionarily conserved noncanonical functions in protein trafficking that are essential for maintaining cellular homeostasis. As a direct target of energy- and nutrient-sensing kinases, ULK/Atg1 is positioned to regulate the distribution and use of cellular resources in response to metabolic cues. In this review, we provide an overview of the molecular mechanisms through which ULK/Atg1 carries out its canonical and noncanonical functions and the signaling pathways that link its function to metabolism. We also highlight potential contributions of ULK/Atg1 in human diseases, including cancer and neurodegeneration.
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AMPK and mTOR regulate autophagy through direct phosphorylation of ULK1
Nature Cell Biology, 2011Co-Authors: Mondira Kundu, Benoit Viollet, Kun-liang GuanAbstract:Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase ULK1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating ULK1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents ULK1 activation by phosphorylating ULK1 Ser 757 and disrupting the interaction between ULK1 and AMPK. This coordinated phosphorylation is important for ULK1 in autophagy induction. Our study has revealed a signalling mechanism for ULK1 regulation and autophagy induction in response to nutrient signalling. A molecular mechanism that links the mTOR and autophagy pathways is now revealed. Depending on nutrient availability, the AMPK and mTOR kinases differentially phosphorylate the autophagy-initiating kinase ULK1 to regulate its activity.
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ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery
Molecular Biology of the Cell, 2009Co-Authors: Chang Hwa Jung, Neil Michael Otto, Seung Hyun Ro, Mondira KunduAbstract:Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.
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Hsp90 regulates ULK1-mediated autophagic clearance of mitochondria
Blood, 2008Co-Authors: Mondira Kundu, Tullia Lindsten, Chia-ying Yang, Kelly Mccastlain, Ji Zhang, Paul Ney, Craig B. ThompsonAbstract:Recent studies have suggested that the serine-threonine kinase ULK1, a mammalian homologue of the yeast autophagy regulator, Atg1, plays an important role in mitochondrial clearance during reticulocyte maturation. In order to gain insight into the regulation and activity of ULK1, we used an unbiased proteomics approach to identify ULK1-interacting proteins. Here, we demonstrate that ULK1 interacts with heat shock protein 90 (Hsp90) and Cdc37, and is among a growing list of proteins whose steady state levels are regulated by this kinase-specific chaperone complex. Treatment of murine embryonic fibroblasts (MEFs) with the HSP90 inhibitor, 17AAG, inhibits the AKT/Tor pathway and induces autophagy despite the decreased steady state levels of ULK1. By contrast, ULK1-deficient MEFs are defective in autophagy induction, as measured by LC3 puncta formation (but not LC3 conversion) and ultrastructural analysis. Exposure of terminally differentiating erythroid cells to HSP90 inhibitors prevents the normal accumulation of ULK1 protein and results in impaired autophagic clearance of organelles, similar to the effect of ULK1 gene deletion. These findings highlight the importance of ULK1 protein levels in terminal erythroid maturation and induction of autophagy and its regulation by the Hsp90/Cdc37 chaperone complex.
