title: SIRT2 interferes with autophagy-mediated degradation of protein aggregates in neuronal cells under proteasome inhibition.
abstract: Abnormal protein aggregates have been suggested as a common pathogenesis of many neurodegenerative diseases. Two well-known protein degradation pathways are responsible for protein homeostasis by balancing protein biosynthesis and degradative processes: the ubiquitin-proteasome system (UPS) and autophagy-lysosomal system. UPS serves as the primary route for degradation of short-lived proteins, but large-size protein aggregates cannot be degraded by UPS. Autophagy is a unique cellular process that facilitates degradation of bulky protein aggregates by lysosome. Recent studies have demonstrated that autophagy plays a crucial role in the pathogenesis of neurodegenerative diseases characterized by abnormal protein accumulation, suggesting that regulation of autophagy may be a valuable therapeutic strategy for the treatment of various neurodegenerative diseases. Sirtuin-2 (SIRT2) is a class III histone deacetylase that is expressed abundantly in aging brain tissue. Here, we report that SIRT2 increases protein accumulation in murine cholinergic SN56 cells and human neuroblastoma SH-SY5Y cells under proteasome inhibition. Overexpression of SIRT2 inhibits lysosome-mediated autophagic turnover by interfering with aggresome formation and also makes cells more vulnerable to accumulated protein-mediated cytotoxicity by MG132 and amyloid beta. Moreover, MG132-induced accumulation of ubiquitinated proteins and p62 as well as cytotoxicity are attenuated in siRNA-mediated SIRT2-silencing cells. Taken together, these results suggest that regulation of SIRT2 could be a good therapeutic target for a range of neurodegenerative diseases by regulating autophagic flux.
authors: College of Pharmacy, CHA University, Seongnam-si, South Korea.
authors: Jiyeong
authors: J
authors: Gal
authors: Yeojin
authors: Y
authors: Bang
authors: Hyun Jin
authors: HJ
authors: Choi
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D059748:Proteolysis; D056565:Sirtuin 2 / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D061988:Proteasome Inhibitors; C474199:SIRT2 protein, human; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2