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

Mol Cell. 2019 May 16;74(4):742-757.e8. doi: 10.1016/j.molcel.2019.03.027. Epub 2019 Apr 9.

Abstract

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.

Keywords: ATG1; ATG7; ULK1; ULK2; VCP; amyotrophic lateral sclerosis; autophagy; inclusion body myopathy; p97; stress granules.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Animals
  • Autophagy / genetics
  • Autophagy-Related Protein-1 Homolog / genetics*
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Humans
  • Inclusion Bodies / genetics
  • Inclusion Bodies / pathology
  • Lysosomal Storage Diseases / genetics*
  • Lysosomal Storage Diseases / metabolism
  • Lysosomal Storage Diseases / pathology
  • Mice
  • Muscular Diseases / genetics*
  • Muscular Diseases / metabolism
  • Muscular Diseases / pathology
  • Phosphorylation / genetics
  • Protein-Serine-Threonine Kinases / genetics*
  • Stress, Physiological / genetics
  • Ubiquitin / genetics
  • Valosin Containing Protein / genetics*

Substances

  • DNA-Binding Proteins
  • TDP-43 protein, mouse
  • Ubiquitin
  • Ulk2 protein, mouse
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • Ulk1 protein, mouse
  • Adenosine Triphosphatases
  • Valosin Containing Protein
  • Vcp protein, mouse

Supplementary concepts

  • Vacuolar myopathy