Site-specific Acetylation of the Proteasome Activator REGγ Directs Its Heptameric Structure and Functions

The proteasome activator REG gamma has been reported to promote degradation of steroid receptor coactivator-3 and cyclin-dependent kinase inhibitors p21, p16, and p19 in a ubiquitin- and ATP-independent manner. A recent comparative analysis of REG gamma expression in mouse and human tissues reveals a unique pattern of REG gamma in specific cell types, suggesting undisclosed functions and biological importance of this molecule. Despite the emerging progress made in REG gamma-related studies, how REG gamma function is regulated remains to be explored. In this study, we report for the first time that REG gamma can be acetylated mostly on its lysine 195 (Lys-195) residue by CREB binding protein (CBP), which can be reversed by sirtuin 1 (SIRT1) in mammalian cells. Site-directed mutagenesis abrogated acetylation at Lys-195 and significantly attenuated the capability of REG gamma to degrade its target substrates, p21 and hepatitis C virus core protein. Mechanistically, acetylation at Lys-195 is important for the interactions between REG gamma monomers and ultimately influences REG gamma heptamerization. Biological analysis of cells containing REG gamma-WT or REG gamma-K195R mutant indicates an impact of acetylation on REG gamma-mediated regulation of cell proliferation and cell cycle progression. These findings reveal a previously unknown mechanism in the regulation of REG gamma assembly and activity, suggesting a potential venue for the intervention of the ubiquitin-independent REG gamma proteasome activity.