A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy

摘要

We demonstrate a role for the NAD-dependent deacetylase Sirti in the regulation of autophagy. In particular, transient increased expression of Sirti is sufficient to stimulate basal rates of autophagy. In addition, we show that Sirt1~(-/-) mouse embryonic fibroblasts do not fully activate autophagy under starved conditions. Reconstitution with wild-type but not a deacetylase-inactive mutant of Sirti restores autophagy in these cells. We further demonstrate that Sirti can form a molecular complex with several essential components of the autophagy machinery, including autophagy genes (Atg)5, Atg7, and Atg8. In vitro, Sirti can, in an NAD-dependent fashion, directly deacetylate these components. The absence of Sirti leads to markedly elevated acetylation of proteins known to be required for autophagy in both cultured cells and in embryonic and neonatal tissues. Finally, we show that Sirt1~(-/-) mice partially resemble Atg5~(-/-) mice, including the accumulation of damaged organelles, disruption of energy ho-meostasis, and early perinatal mortality. Furthermore, the in utero delivery of the metabolic substrate pyruvate extends the survival of Sirt1~(-/-) pups. These results suggest that the Sirti deacetylase is an important in vivo regulator of autophagy and provide a link between sirtuin function and the overall cellular response to limited nutrients.