2. Academic Validation
  3. Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination

Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination

  • Cell Rep. 2017 Apr 4;19(1):188-202. doi: 10.1016/j.celrep.2017.03.030.
YouJin Lee 1,  Tsui-Fen Chou 2,  Sara K Pittman 1,  Amy L Keith 1,  Babak Razani 3,  Conrad C Weihl 4
Affiliations

Affiliations

  • 1 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 2 Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA 90502, USA.
  • 3 Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 4 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: [email protected].
PMID: 28380357 DOI: 10.1016/j.celrep.2017.03.030
Abstract

p62/SQSTM1 (p62) is a scaffolding protein that facilitates the formation and degradation of ubiquitinated aggregates via its self-interaction and ubiquitin binding domains. The regulation of this process is unclear but may relate to the post-translational modification of p62. In the present study, we find that Keap1/Cullin3 ubiquitinates p62 at lysine 420 within its UBA domain. Substitution of lysine 420 with an arginine diminishes p62 sequestration and degradation activity similar what is seen when the UBA domain is deleted. Overexpression of Keap1/Cullin3 in p62-WT-expressing cells increases ubiquitinated inclusion formation and p62's association with LC3 and rescues proteotoxicity. This effect is not seen in cells expressing a mutant p62 that fails to interact with Keap1. Interestingly, p62 disease mutants have diminished or absent UBA domain ubiquitination. These data suggest that the ubiquitination of p62's UBA domain at lysine 420 may regulate p62's function and be disrupted in p62-associated disease.

Keywords

SQSTM1/p62; aggregaphagy; autophagy; neurodegeneration; ubiquitin.

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