Suchergebnisse

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.).

Sirtuins are NAD+-dependent deacetylases that facilitate cellular stress response. They include SirT6, which protects genome stability and regulates metabolic homeostasis through gene silencing, and whose loss induces an accelerated aging phenotype directly linked to hyperactivation of the NF-κB pathway. Here we show that SirT6 binds to the H3K9me3-specific histone methyltransferase Suv39h1 and induces monoubiquitination of conserved cysteines in the PRE-SET domain of Suv39h1. Following activation of NF-κB signaling Suv39h1 is released from the IκBα locus, subsequently repressing the NF-κB pathway. We propose that SirT6 attenuates the NF-κB pathway through IκBα upregulation via cysteine monoubiquitination and chromatin eviction of Suv39h1. We suggest a mechanism based on SirT6-mediated enhancement of a negative feedback loop that restricts the NF-κB pathway. ; This work was supported by the Fundació La Marató de TV3 (20133810 to A.V.), the Spanish Ministry of Economy and competitiveness-MINECO (SAF2011-25860, SAF2014-55964R to A.V.) confunded by FEDER funds/European Regional Development Fund (ERDF)-a way to Build Europe, and the Catalan government agency AGAUR (2009-SGR-914 to A.V.) The IDIBELL Proteomics Unit belongs to ProteoRed, PRB2-ISCIII, and is supported by grant PT13/0001/0033 and Cellex Foundation. S.B.B. is the recipient of a 13FIS037 fellowship.