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SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1.1

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE128894 | GEO | 2019/08/07

REPOSITORIES: GEO

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SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1.1 (RNA-seq)

Project description:Sirtuins are key players in the response to oxidative, metabolic and genotoxic stress, and are involved in genome stability, metabolic homeostasis and aging. Originally described as NAD+-dependent deacetylases, some sirtuins are also characterized by poorly understood mono-ADP-ribosyltransferase (MADPRT) activity. Here we report that the deacetylase SirT7 is a dual sirtuin as it also features auto-MADPRT activity. Molecular and structural evidence suggests that this novel activity occurs at a second previously undefined active site that is physically separated in another domain. Specific abrogation of this activity alters SirT7 chromatin distribution, suggesting a role for this modification in SirT7 chromatin binding specificity and localization. Our studies uncover an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader macroH2A1.1, a histone variant involved in chromatin organization, metabolism and differentiation. Glucose starvation (GS) boosts this interaction and promotes SirT7 re-localization intergenic regions in a macroH2A1-dependent manner, which is required for specific up- or downregulation of a subset of nearby genes upon GS in primary cells and in vivo in the livers of calorie-restricted (CR) Wt and SirT7-/- mice. The level of expression of these genes decreases with age in SirT7-deficient mice, reinforcing the link between Sirtuins, CR and aging. Our work provides a novel perspective about sirtuin duality and suggests a key role for SirT7/macroH2A1.1 axis in mammalian glucose homeostasis, calorie restriction signaling and aging.

2019-08-07 | GSE128893 | GEO

SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1.1 (ChIP-seq)

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

Project description: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.

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SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1.1

Project description:SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1.1

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SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1.1 (RNA-seq)

Project description:SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1.1 (RNA-seq)

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SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1.1 (ChIP-seq)

Project description:SirT7 auto-ADPribosylation regulates glucose starvation response through macroH2A1.1 (ChIP-seq)

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Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition.

Project description:Hexokinase-II (HK-II) catalyzes the first step of glycolysis and also functions as a protective molecule; however, its role in protective autophagy has not been determined. Results showed that inhibition of HK-II diminished, while overexpression of HK-II potentiated, autophagy induced by glucose deprivation in cardiomyocyte and noncardiomyocyte cells. Immunoprecipitation studies revealed that HK-II binds to and inhibits the autophagy suppressor, mTOR complex 1 (TORC1), and that this binding was increased by glucose deprivation. The TOS motif, a scaffold sequence responsible for binding TORC1 substrates, is present in HK-II, and mutating it blocked its ability to bind to TORC1 and regulate protective autophagy. The transition from glycolysis to autophagy appears to be regulated by a decrease in glucose-6 phosphate. We suggest that HK-II binds TORC1 as a decoy substrate and provides a previously unrecognized mechanism for switching cells from a metabolic economy, based on plentiful energy, to one of conservation, under starvation.

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