title: The REGγ proteasome regulates hepatic lipid metabolism through inhibition of autophagy.
abstract: The ubiquitin-proteasome and autophagy-lysosome systems are major proteolytic pathways, whereas function of the Ub-independent proteasome pathway is yet to be clarified. Here, we investigated roles of the Ub-independent REGγ-proteasome proteolytic system in regulating metabolism. We demonstrate that mice deficient for the proteasome activator REGγ exhibit dramatic autophagy induction and are protected against high-fat diet (HFD)-induced liver steatosis through autophagy. Molecularly, prevention of steatosis in the absence of REGγ entails elevated SirT1, a deacetylase regulating autophagy and metabolism. REGγ physically binds to SirT1, promotes its Ub-independent degradation, and inhibits its activity to deacetylate autophagy-related proteins, thereby inhibiting autophagy under normal conditions. Moreover, REGγ and SirT1 dissociate from each other through a phosphorylation-dependent mechanism under energy-deprived conditions, unleashing SirT1 to stimulate autophagy. These observations provide a function of the REGγ proteasome in autophagy and hepatosteatosis, underscoring mechanistically a crosstalk between the proteasome and autophagy degradation system in the regulation of lipid homeostasis.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, 200241, China; Department of Molecular and Cellular Biology, Department of Medicine, The Dan L. Duncan Cancer Center, The Diabetes Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Shuxian
authors.initials: S
authors.lastname: Dong
authors.forename: Caifeng
authors.initials: C
authors.lastname: Jia
authors.forename: Shengping
authors.initials: S
authors.lastname: Zhang
authors.forename: Guangjian
authors.initials: G
authors.lastname: Fan
authors.forename: Yubing
authors.initials: Y
authors.lastname: Li
authors.forename: Peipei
authors.initials: P
authors.lastname: Shan
authors.forename: Lianhui
authors.initials: L
authors.lastname: Sun
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Xiao
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jinqin
authors.initials: J
authors.lastname: Liu
authors.forename: Haibing
authors.initials: H
authors.lastname: Wei
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Zhai
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Fuli
authors.initials: F
authors.lastname: Jia
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.forename: Dean P
authors.initials: DP
authors.lastname: Edwards
authors.forename: Shixia
authors.initials: S
authors.lastname: Huang
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Li
authors.forename: Chuangui
authors.initials: C
authors.lastname: Wang
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D002460:Cell Line; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000209:etiology; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D056564:Sirtuin 1 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D001324:Autoantigens; C099558:Ki antigen; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1