Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination.
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.
['Lee|YouJin|Y|', 'Chou|Tsui-Fen|TF|', 'Pittman|Sara K|SK|', 'Keith|Amy L|AL|', 'Razani|Babak|B|', 'Weihl|Conrad C|CC|']
D019943:Amino Acid Substitution D001343:Autophagy D002478:Cells, Cultured D044842:Cullin Proteins D003517:Cyclopentanes D006801:Humans D002479:Inclusion Bodies D047908:Intracellular Signaling Peptides and Proteins D000072019:Kelch-Like ECH-Associated Protein 1 D008239:Lysine D008869:Microtubule-Associated Proteins D011485:Protein Binding D011743:Pyrimidines D000071456:Sequestosome-1 Protein D025801:Ubiquitin D044767:Ubiquitin-Protein Ligases D054875:Ubiquitination
ubiquitin SQSTM1/p62 aggregaphagy autophagy neurodegeneration