Format

Send to

Choose Destination
Mol Cell. 2019 Apr 3. pii: S1097-2765(19)30231-X. doi: 10.1016/j.molcel.2019.03.027. [Epub ahead of print]

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

Author information

1
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
3
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
4
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
5
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Department of Neurology, University of Tennessee Heath Science Center, Memphis, TN 38163, USA.
8
Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
9
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
10
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: mondira.kundu@stjude.org.

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

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center