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

Lee, YouJin et al.

Cell reports. Volume 19:Number 1 (2017, April 4th); pp 188-202 -- Elsevier

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  • Title:
    Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination
  • Author: Lee, YouJin;
    Chou, Tsui-Fen;
    Pittman, Sara K.;
    Keith, Amy L.;
    Razani, Babak;
    Weihl, Conrad C.
  • Found In: Cell reports. Volume 19:Number 1 (2017, April 4th); pp 188-202
  • Journal Title: Cell reports
  • Subjects: Biology--Periodicals; Life sciences--Periodicals; SQSTM1/p62--ubiquitin--autophagy--neurodegeneration--aggregaphagy; Dewey: 571.6; Dewey: 571.6
  • Rights: Licensed
  • Publication Details: Elsevier
  • Abstract: Summary 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. Graphical Abstract Highlights p62/SQSTM1 is ubiquitinated by the Keap1/Cul3 complex within its UBA domain UBA domain ubiquitination increases p62's sequestering activity and degradation p62-associated disease mutants diminish UBA domain ubiquitination and cell viability 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.
  • Identifier: System Number: ETOCvdc_100063241423.0x000001; Journal ISSN: 2211-1247; 10.1016/j.celrep.2017.03.030
  • Publication Date: 2017
  • Physical Description: Electronic
  • UIN: ETOCvdc_100063241423.0x000001

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