The REGγ proteasome regulates hepatic lipid metabolism through inhibition of autophagy

Cell Metab. 2013 Sep 3;18(3):380-91. doi: 10.1016/j.cmet.2013.08.012.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / genetics
  • Autoantigens / metabolism*
  • Autophagy*
  • Cell Line
  • Diet, High-Fat
  • Fatty Liver / etiology
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Lipid Metabolism
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Proteasome Endopeptidase Complex / deficiency
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Sirtuin 1 / metabolism
  • Ubiquitin / metabolism*


  • Autoantigens
  • Ki antigen
  • Ubiquitin
  • Proteasome Endopeptidase Complex
  • Sirt1 protein, mouse
  • Sirtuin 1