SirT7 auto-ADP-ribosylation regulates glucose starvation response through mH2A1

Abstract

Sirtuins are key players of metabolic stress response. Originally described as deacetylases, some sirtuins also exhibit poorly understood mono-adenosine 5'-diphosphate (ADP)-ribosyltransferase (mADPRT) activity. We report that the deacetylase SirT7 is a dual sirtuin, as it also features auto-mADPRT activity. SirT7 mADPRT occurs at a previously undefined active site, and its abrogation alters SirT7 chromatin distribution. We identify an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions. SirT7 promotes mH2A1 enrichment in a subset of nearby genes, many of them involved in second messenger signaling, resulting in their specific up- or down-regulation. The expression profile of these genes under calorie restriction is consistently abrogated in SirT7-deficient mice, resulting in impaired activation of autophagy. Our work provides a novel perspective on sirtuin duality and suggests a role for SirT7/mH2A1.1 axis in glucose homeostasis and aging. ; This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2011-25860, SAF2014-55964R, and SAF2017-88975R to A.V.; SAF2016-77830R to M.O.; and CTQ2016-80364-P to E.S.) and cofunded by FEDER funds/European Regional Development Fund (ERDF)–A Way to Build Europe, the Catalan government agency AGAUR (2014-SGR400 and 2017-SGR148 to A.V. and 2017-SGR595 to E.S.), a grant from Rutgers Human Genetics Institute of New Jersey (J.T. and L.S.), the German Center for Cardiovascular Research (DZHK), and the Deutsche Forschungsgemeinschaft (DFG SFB TRR81 A02 and SFB 1213 TP B02 to A.I. and T.B.).