Deacetylation of FoxO by Sirt1 Plays an Essential Role in Mediating Starvation-Induced Autophagy in Cardiac Myocytes.
BACKGROUND
autophagy, a bulk degradation process of cytosolic proteins and organelles, is protective during nutrient starvation in cardiomyocytes (CMs). However, the underlying signaling mechanism mediating autophagy is not well understood.


OBJECTIVE
we investigated the role of FoxOs and its posttranslational modification in mediating starvation-induced autophagy.


RESULTS
glucose deprivation (GD) increased autophagic flux in cultured CMs, as evidenced by increased mRFP-GFP-LC3 puncta and decreases in p62, which was accompanied by upregulation of Sirt1 and FoxO1. Overexpression of either Sirt1 or FoxO1 was sufficient for inducing autophagic flux, whereas both Sirt1 and FoxO1 were required for GD-induced autophagy. GD increased deacetylation of FoxO1, and Sirt1 was required for GD-induced deacetylation of FoxO1. Overexpression of FoxO1(3A/LXXAA), which cannot interact with Sirt1, or p300, a histone acetylase, increased acetylation of FoxO1 and inhibited GD-induced autophagy. FoxO1 increased expression of Rab7, a small GTP-binding protein that mediates late autophagosome-lysosome fusion, which was both necessary and sufficient for mediating FoxO1-induced increases in autophagic flux. Although cardiac function was maintained in control mice after 48 hours of food starvation, it was significantly deteriorated in mice with cardiac-specific overexpression of FoxO1(3A/LXXAA), those with cardiac-specific homozygous deletion of FoxO1 (c-FoxO1(-/-)), and beclin1(+/-) mice, in which autophagy is significantly inhibited.


CONCLUSIONS
these results suggest that Sirt1-mediated deacetylation of FoxO1 and upregulation of Rab7 play an important role in mediating starvation-induced increases in autophagic flux, which in turn plays an essential role in maintaining left ventricular function during starvation.
Hariharan
Nirmala
N
University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Department of Cell Biology and Molecular Medicine, Newark, USA.
Maejima
Yasuhiro
Y
Nakae
Jun
J
Paik
Jihye
J
Depinho
Ronald A
RA
Sadoshima
Junichi
J
D000107:Acetylation; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D056564:Sirtuin 1 / Q000378:metabolism*; D013217:Starvation / Q000473:pathology*; D016277:Ventricular Function, Left; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D020691:rab GTP-Binding Proteins