A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy.
We demonstrate a role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. In particular, transient increased expression of Sirt1 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 Sirt1 restores autophagy in these cells. We further demonstrate that Sirt1 can form a molecular complex with several essential components of the autophagy machinery, including autophagy genes (Atg)5, Atg7, and Atg8. In vitro, Sirt1 can, in an NAD-dependent fashion, directly deacetylate these components. The absence of Sirt1 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 homeostasis, 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 Sirt1 deacetylase is an important in vivo regulator of autophagy and provide a link between sirtuin function and the overall cellular response to limited nutrients.
Lee
In Hye
IH
Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Cao
Liu
L
Mostoslavsky
Raul
R
Lombard
David B
DB
Liu
Jie
J
Bruns
Nicholas E
NE
Tsokos
Maria
M
Alt
Frederick W
FW
Finkel
Toren
T
D000107:Acetylation; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D002460:Cell Line; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics; D010641:Phenotype; D034741:RNA, Small Interfering / Q000494:pharmacology; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000502:physiology*; D013217:Starvation; D015996:Survival Rate; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics
C502778:ATG5 protein, human; C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes