Sirtuin 2 controls global protein synthesis by regulating Rheb-GTPase

Upregulated global protein synthesis is associated with the development and progression of several 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 deacylase, negatively regulates global protein synthesis by inhibiting the mTORC1 pathway via deacetylating Rheb and promoting Rheb degradation. Our in vitro results suggest that SIRT2 deficiency increases protein synthesis, whereas SIRT2 overexpression suppresses protein synthesis. SIRT2-deficient mice exhibit age-associated and neurohormone-induced cardiac hypertrophy. Here, we report increased global protein synthesis in the hearts of young SIRT2-deficient mice, which may contribute to the development of cardiac hypertrophy. Conversely, cardiac-specific overexpression of SIRT2 reduces global protein synthesis in mice hearts. Mechanistically, SIRT2 binds to and deacetylates Rheb at K151 residue to enhance ubiquitin-proteosome-mediated degradation of Rheb. Depletion of Rheb rescues the increased protein synthesis in SIRT2-inhibited conditions. Our findings suggest that SIRT2 activation can be a potential therapeutic for treating diseases associated with increased protein synthesis.