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Bo Wang - One of the best experts on this subject based on the ideXlab platform.

  • ulk1 and ULK2 regulate stress granule disassembly through phosphorylation and activation of vcp p97
    Molecular Cell, 2019
    Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Ashutosh Mishra, Amber L Ward, Honghu Quan, Sadie Miki Sakurada
    Abstract:

    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.

  • ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97
    Molecular Cell, 2019
    Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Ashutosh Mishra, Amber L Ward, Honghu Quan, Sadie Miki Sakurada
    Abstract:

    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.

  • the autophagy inducing kinases ulk1 and ULK2 regulate axon guidance in the developing mouse forebrain via a noncanonical pathway
    Autophagy, 2018
    Co-Authors: Bo Wang, Rekha Iyengar, Christopher Wright, Xiujie Liharms, Alfonso Lavado, Linda Horner, Mao Yang, Junlin Guan, Sharon Frase, Douglas R Green
    Abstract:

    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.

  • The autophagy-inducing kinases, ULK1 and ULK2, regulate axon guidance in the developing mouse forebrain via a noncanonical pathway.
    Autophagy, 2017
    Co-Authors: Bo Wang, Rekha Iyengar, Xiu Jie Li-harms, Christopher Wright, Alfonso Lavado, Linda Horner, Mao Yang, Junlin Guan, Sharon Frase
    Abstract:

    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...

  • Canonical and noncanonical functions of ULK/Atg1
    Current Opinion in Cell Biology, 2017
    Co-Authors: Bo Wang, Mondira Kundu
    Abstract:

    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.

  • ulk1 and ULK2 regulate stress granule disassembly through phosphorylation and activation of vcp p97
    Molecular Cell, 2019
    Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Ashutosh Mishra, Amber L Ward, Honghu Quan, Sadie Miki Sakurada
    Abstract:

    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.

  • ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97
    Molecular Cell, 2019
    Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Ashutosh Mishra, Amber L Ward, Honghu Quan, Sadie Miki Sakurada
    Abstract:

    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.

James Messing - One of the best experts on this subject based on the ideXlab platform.

  • ulk1 and ULK2 regulate stress granule disassembly through phosphorylation and activation of vcp p97
    Molecular Cell, 2019
    Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Ashutosh Mishra, Amber L Ward, Honghu Quan, Sadie Miki Sakurada
    Abstract:

    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.

  • ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97
    Molecular Cell, 2019
    Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Ashutosh Mishra, Amber L Ward, Honghu Quan, Sadie Miki Sakurada
    Abstract:

    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.

  • ulk1 and ULK2 regulate stress granule disassembly through phosphorylation and activation of vcp p97
    Molecular Cell, 2019
    Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Ashutosh Mishra, Amber L Ward, Honghu Quan, Sadie Miki Sakurada
    Abstract:

    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.

  • ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97
    Molecular Cell, 2019
    Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Ashutosh Mishra, Amber L Ward, Honghu Quan, Sadie Miki Sakurada
    Abstract:

    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.

  • The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis
    Molecular Cell, 2016
    Co-Authors: Bo Wang, E.b. Frankel, Liang Ge, Lu Xu, Rekha Iyengar, Xiu Jie Li-harms, Christopher Wright, Timothy I. Shaw, Tullia Lindsten
    Abstract:

    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.

Honghu Quan - One of the best experts on this subject based on the ideXlab platform.

  • ulk1 and ULK2 regulate stress granule disassembly through phosphorylation and activation of vcp p97
    Molecular Cell, 2019
    Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Ashutosh Mishra, Amber L Ward, Honghu Quan, Sadie Miki Sakurada
    Abstract:

    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.

  • ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97
    Molecular Cell, 2019
    Co-Authors: Bo Wang, Timothy I. Shaw, Brian A Maxwell, Youngdae Gwon, James Messing, Ashutosh Mishra, Amber L Ward, Honghu Quan, Sadie Miki Sakurada
    Abstract:

    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.