Proteasome Activator REGγ Regulates Autophagy Via Effects On SirT1Deacetylase

Autophagy and the ubiquitin-proteasome systems are two major protein degradation pathways in eukaryotic cells. SirT1is an NAD-dependent deacetylase that plays important roles in regulating longevity and stress response. Recent studies entail SirT1as an important regulator of autophagy._However, the mechanisms involved in the regulation of SirT1induced autophagy remain elusive. REGγ, a20S proteasome activator mediating ubiquitin-independent proteasomal protein degradation, plays crucial roles in regulating cell proliferation and apoptosis. Here we show that REGγ deficiency triggers autophagy. REGγ directly binds to and promotes SirT1degradation, which reduces the interaction between SirT1and autophagy complex, leads to autophagy inhibition at normal conditions. Furthermore, energy deprivation strengthens SirT1phosphorylation by AMPK, which prevents REGγ-SirT1interactions and releases SirT1to enhance autophagy, suggesting a function of REGγ as a molecular switch between autophagy and the proteasomal protein degradation pathways. Our results provide novel insights into the mechanisms in the regulation of autophagy under normal and stress conditions.