Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Autophagy is essential for cellular homeostasis.
• The precise mechanisms initiating autophagy, especially under stress, require further elucidation.

Purpose of the Study:

• To define the molecular mechanism of autophagy initiation triggered by glutamine deprivation and hypoxia.
• To investigate the role of ARD1, PGK1, and Beclin1 in autophagy and brain tumorigenesis.

Main Methods:

• Investigated the effect of glutamine deprivation and hypoxia on mTOR-mediated ARD1 phosphorylation.
• Analyzed ARD1-dependent PGK1 acetylation and PGK1-mediated Beclin1 phosphorylation.
• Assessed the impact of these modifications on VPS34 activity and autophagy induction.
• Correlated PGK1 acetylation and Beclin1 phosphorylation with patient prognosis in glioblastoma.

Main Results:

• Glutamine deprivation and hypoxia inhibit mTOR-mediated ARD1 S228 phosphorylation.
• This leads to ARD1-dependent PGK1 K388 acetylation and PGK1-mediated Beclin1 S30 phosphorylation.
• PGK1 acetylation and Beclin1 phosphorylation enhance VPS34 activity, driving autophagy.
• These events are crucial for hypoxia- and glutamine deprivation-induced autophagy and brain tumorigenesis.
• PGK1 K388 acetylation and Beclin1 S30 phosphorylation correlate with poor glioblastoma prognosis.

Conclusions:

• A novel pathway links metabolic stress to autophagy initiation through ARD1-PGK1-Beclin1 axis.
• The metabolic enzyme PGK1 possesses protein kinase activity crucial for autophagy.
• The interplay between autophagy and cell metabolism is critical for homeostasis and tumorigenesis.