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

Publication date: 4 April 2017
Source:Cell Reports, Volume 19, Issue 1
Author(s): YouJin Lee, Tsui-Fen Chou, Sara K. Pittman, Amy L. Keith, Babak Razani, Conrad C. Weihl
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.

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Teaser

In autophagy, the adaptor protein p62/SQSTM1 selectively sequesters ubiquitinated protein aggregates into inclusion bodies and recruits them to the growing autophagosome. Lee et al. show that ubiquitination of p62 within its ubiquitin-binding UBA domain enhances p62's sequestering activity and autophagic degradation.


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