Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination
| Autor: | Amy L. Keith, Conrad C. Weihl, Sara K. Pittman, Tsui-Fen Chou, YouJin Lee, Babak Razani |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Scaffold protein Arginine Ubiquitin binding Ubiquitin-Protein Ligases Mutant Lysine SQSTM1/p62 Cyclopentanes General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Ubiquitin aggregaphagy Sequestosome-1 Protein Autophagy Humans lcsh:QH301-705.5 Cells Cultured Inclusion Bodies Kelch-Like ECH-Associated Protein 1 biology neurodegeneration Intracellular Signaling Peptides and Proteins Ubiquitination Cullin Proteins Molecular biology KEAP1 Cell biology 030104 developmental biology Pyrimidines Proteotoxicity Amino Acid Substitution lcsh:Biology (General) biology.protein Microtubule-Associated Proteins Protein Binding |
| Zdroj: | Cell Reports, Vol 20, Iss 8, p 1994 (2017) Cell Reports, Vol 19, Iss 1, Pp 188-202 (2017) |
| ISSN: | 2211-1247 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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