Proteotoxic Stress Induces Phosphorylation of p62/SQSTM1 by ULK1 to Regulate Selective Autophagic Clearance of Protein Aggregates

• DOI: 10.1371/journal.pgen.1004987
• Publication Date: 2015-02-27T18:47:51Z
• Authors: Junghyun Lim; M. Lenard Lachenm...; Shuai Wu; Wenchao Liu; Mondira Kundu; Rong Wang; Masaaki Komatsu; Young J. Oh; Yanxiang Zhao; Zhenyu Yue
• Keywords: Proteostasis; Autophagy-related protein 13; ULK1; BAG3; Sequestosome 1

Disruption of proteostasis, or protein homeostasis, is often associated with aberrant accumulation misfolded proteins aggregates. Autophagy offers protection to cells by removing toxic aggregates and injured organelles in response proteotoxic stress. However, the exact mechanism whereby autophagy recognizes degrades aggregated has yet be elucidated. Mounting evidence demonstrates selectivity autophagy, which mediated through receptor (e.g. p62/SQSTM1) linking cargos autophagosomes. Here we report that stress imposed proteasome inhibition expression polyglutamine expanded huntingtin (polyQ-Htt) induces p62 phosphorylation at its ubiquitin-association (UBA) domain regulates binding ubiquitinated proteins. We find autophagy-related kinase ULK1 phosphorylates a novel site S409 UBA domain. Interestingly, does not occur upon nutrient starvation, spite role canonical signaling. also S405, while critically S405 phosphorylation. destabilizes dimer interface, increases affinity ubiquitin. Furthermore, lack causes p62, localization clearance polyQ-Htt. Therefore, our data provide mechanistic insights into regulation selective Our study suggests potential drug target developing autophagy-based therapeutics for treatment proteinopathies including Huntington’s disease.