Sirtuin 2 inhibits global protein synthesis via Rheb-GTPase degradation.

Increased global protein synthesis is associated with the development and progression of several aging-related diseases and disorders. Strategies like calorie restriction and pharmacological inhibition of protein synthesis have exhibited health-promoting effects. However, the complex molecular events that regulate global protein synthesis are not completely understood. Here, we report that SIRT2, a histone deacetylase, negatively regulates global protein synthesis by inhibiting the mTORC1 pathway via deacetylating Rheb and promoting its degradation. Our in vitro results suggest that SIRT2 deficiency increases protein synthesis, whereas SIRT2 overexpression suppresses protein synthesis. SIRT2-deficient mice exhibit increased global protein synthesis in the hearts, which may contribute to the development of cardiac hypertrophy. Conversely, cardiac-specific overexpression reduces global protein synthesis in the hearts of SIRT2 transgenic mice. Mechanistically, SIRT2 binds to and deacetylates Rheb at K151 residue to enhance ubiquitin-proteosome-mediated degradation of Rheb. Depletion of Rheb rescues increased protein synthesis in SIRT2-inhibited conditions. Our findings suggest that SIRT2 activation could be a potential therapeutic strategy for treating diseases associated with increased protein synthesis.