AMPK-Dependent Phosphorylation of GAPDH Triggers Sirt1 Activation and Is Necessary for Autophagy upon Glucose Starvation

Abstract

Eukaryotes initiate autophagy to cope with the lack of external nutrients, which requires the activation of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase Sirtuin 1 (Sirt1). However, the mechanisms underlying the starvation-induced Sirt1 activation for autophagy initiation remain unclear. Here, we demonstrate that glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a conventional glycolytic enzyme, is a critical mediator of AMP-activated protein kinase (AMPK)-driven Sirt1 activation. Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated. Preventing this shift of GAPDH abolishes Sirt1 activation and autophagy, while enhancing it, through overexpression of nuclear-localized GAPDH, increases Sirt1 activation and autophagy. GAPDH is thus a pivotal and central regulator of autophagy under glucose deficiency, undergoing AMPK-dependent phosphorylation and nuclear translocation to activate Sirt1 deacetylase activity.

BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function

“…Previous studies have shown that during starvation, SIRT1 separates from the inhibitory molecule CCAR2/DBC1, and then gets activated by AMP-activated protein kinase (AMPK). 11,12 In the present study, BRD4 is found to form a complex with SIRT1 and CCAR2. Starvation can disrupt the SIRT1-CCAR2 interaction, whereas inhibition or silencing of AMPK does not.…”

Metabolomics reveals critical adrenergic regulatory checkpoints in glycolysis and pentose–phosphate pathways in embryonic heart

“…One potential regulatory mechanism following adrenergic stimulation is phosphorylation of GAPDH to increase activity (40,41). Studies have shown several kinases regulated by adrenergic stimulation; including Akt/PKB, CaMKIIβ, PKC, and AMPK, phosphorylate GAPDH to enhance activity (42)(43)(44)(45). Thus, the observed decrease in the ration of phosphorylated to total GAPDH protein in adrenergic-deficient embryos is consistent with the decreased enzymatic activity observed for GAPDH in these embryos.…”

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

“…The role of the PACS proteins in the nucleus is just beginning to be understood. Notably, PACS-2 is the most recent addition to a small collection of proteins that regulate SIRT1, which include deleted in breast cancer 1 (DBC1; also known as CCAR2), active regulator of SIRT1 (AROS; also known as RPS19BP1) and the moonlighting protein GAPDH (Kim et al, 2007(Kim et al, , 2008Atkins et al, 2014;Chang et al, 2015). It will be important to determine whether PACS-2 acts in the same or different pathways to the other SIRT1 regulators and whether PACS-2 or PACS-1 regulates HDACs in addition to SIRT1.…”