A new study uncovers a link between the proteasome and autophagy in lipid metabolism and identifies the ubiquitin-independent REGγ proteasome system as a key metabolic regulator (Cell Metab. 18, 380–391).

Shuxian Dong et al. showed that knocking out the REGγ proteasome in mice led to autophagy and could protect mice from high-fat diet (HFD)-induced lipid steatosis in the liver. Delving into the underlying mechanism for the effects of REGγ, the authors found that in normal conditions it binds sirtuin 1 (SirT1), a protein deacetylase that has been described to alter lifespan and cellular metabolism. REGγ binding of SirT1 promotes ubiquitin-independent degradation of SirT1. This displaces the autophagy-related Atg proteins from SirT1 and increases their acetylation, thus inhibiting autophagy. In conditions of energy deprivation, REGγ dissociates from SirT1, thus allowing SIRT1 to interact with its Atg targets and upregulate autophagy.

The researchers then showed that treating HFD-fed REGγ-knockout mice with an autophagy inhibitor increased lipid droplet accumulation in the liver to similar levels to as in HFD-fed wild-type mice, suggesting that autophagy is required for the protection against hepatic steatosis elicited by knocking out REGγ.

This identification of REGγ as a regulator of autophagy and lipid metabolism could lead to approaches to target REGγ for therapeutic benefit in a diverse range of metabolic disorders.