4.8 Article

ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97

期刊

MOLECULAR CELL
卷 74, 期 4, 页码 742-+

出版社

CELL PRESS
DOI: 10.1016/j.molcel.2019.03.027

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资金

  1. Cancer Center Support Grant from the National Institutes of Health (NIH) [P30 CA021765]
  2. American Lebanese Syrian Associated Charities (ALSAC)
  3. ALSAC
  4. NIH [R01 MH115058, HL114697, R01 GM114260, R35 NS097974]
  5. Howard Hughes Medical Institute
  6. Robert Packard Center for ALS Research

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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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