Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy

Abstract

SUMMARY Autophagy is crucial for maintaining cell homeostasis. However, the precise mechanism underlying autophagy initiation remains to be defined. Here, we demonstrate that glutamine deprivation and hypoxia result in inhibition of mTOR-mediated acetyl-transferase ARD1 S228 phosphorylation, leading to ARD1-dependent phosphoglycerate kinase 1 (PGK1) K388 acetylation and subsequent PGK1-mediated Beclin1 S30 phosphorylation. This phosphorylation enhances ATG14L-associated class III phosphatidylinositol 3-kinase VPS34 activity by increasing the binding of phosphatidylinositol to VPS34. ARD1-dependent PGK1 acetylation and PGK1-mediated Beclin1 S30 phosphorylation are required for glutamine deprivation- and hypoxia-induced autophagy and brain tumorigenesis. Furthermore, PGK1 K388 acetylation levels correlate with Beclin1 S30 phosphorylation levels and poor prognosis in glioblastoma patients. Our study unearthed an important mechanism underlying cellular stress-induced autophagy initiation, in which the protein kinase activity of the metabolic enzyme PGK1 plays an instrumental role, and revealed the significance of the mutual regulation of autophagy and cell metabolism in maintaining cell homeostasis.

Lactobacillus johnsonii L531 ameliorates enteritis via elimination of damaged mitochondria and suppression of SQSTM1‐dependent mitophagy in a Salmonella infantis model of piglet diarrhea

“…During the initiation of autophagy, autophagosome nucleation requires a complex that contains Beclin 1 . Cardiac‐specific overexpression of Beclin 1 promoted autophagy and alleviated inflammation after LPS challenge.…”

“…38 During the initiation of autophagy, autophagosome nucleation requires a complex that contains Beclin 1. 39 Cardiacspecific overexpression of Beclin 1 promoted autophagy and alleviated inflammation after LPS challenge. Beclin 1 depletion led to degradation of p62 and autophagic flux blunted in LPS-challenged mice.…”

Benzene induces haematotoxicity by promoting deacetylation and autophagy

“…Autophagy can be regulated by posttranslational modifications including phosphorylation, ubiquitination, and acetylation. 12,14,15 Our previous work has shown that hypoacetylation of histone H3 and H4 in Topo IIα promoter can lead to reduced expression of Topo IIα in patients with chronic benzene exposure, 16 but the relationship of between hypoacetylation and autophagy remains unknown. Accumulating evidence shows that acetylation of autophagic components is rather complex and mainly regulated by a major acetyltransferase p300 and a NAD + -dependent deacetylase Sirt1.…”

Vps34 Kinase Domain Dynamics Regulate the Autophagic PI 3-Kinase Complex

“…The N-terminal regulatory sequences of ATG14 and BECN1 have not been visualized in either the EM or crystal structures, but are presumably attached to the base. These regions contain the binding sites for important regulators of PI3KC3 such as Bcl-2 (Oberstein et al, 2007; Pattingre et al, 2005) and NRBF2 (Ohashi et al, 2016; Young et al, 2016) and important sites of regulatory phosphorylation by ULK1, AMPK, DAPK, MAPKAP2, and PGK1 (Kim et al, 2013; Qian et al, 2017; Russell et al, 2013; Wei et al, 2015). The VPS34 catalytic subunit makes almost no contacts between the regulatory BECN1 and ATG14 subunits.…”