| First Author | Dong S | Year | 2013 |
| Journal | Cell Metab | Volume | 18 |
| Issue | 3 | Pages | 380-91 |
| PubMed ID | 24011073 | Mgi Jnum | J:203816 |
| Mgi Id | MGI:5528775 | Doi | 10.1016/j.cmet.2013.08.012 |
| Citation | Dong S, et al. (2013) The REGgamma proteasome regulates hepatic lipid metabolism through inhibition of autophagy. Cell Metab 18(3):380-91 |
| abstractText | 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 REGgamma-proteasome proteolytic system in regulating metabolism. We demonstrate that mice deficient for the proteasome activator REGgamma 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 REGgamma entails elevated SirT1, a deacetylase regulating autophagy and metabolism. REGgamma 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, REGgamma 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 REGgamma proteasome in autophagy and hepatosteatosis, underscoring mechanistically a crosstalk between the proteasome and autophagy degradation system in the regulation of lipid homeostasis. |
