Journal
DEVELOPMENTAL CELL
Volume 56, Issue 13, Pages 1961-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2021.05.010
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Funding
- UK Dementia Research Institute (MRC)
- UK Dementia Research Institute (Alzheimer's Research UK)
- Roger de Spoelberch Foundation
- Gates Cambridge Scholarship
- UK Dementia Research Institute (Alzheimer's Society)
- MRC [UKDRI-2002] Funding Source: UKRI
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In response to glucose starvation, ULK1 activation by AMPK phosphorylates PIKfyve on S1548, leading to increased synthesis of the phospholipid PI(5)P and formation of PI(5)P-containing autophagosomes. This ULK1-mediated process enhances autophagy flux and reduces autophagy substrate levels.
Autophagy is an essential catabolic process induced to provide cellular energy sources in response to nutrient limitation through the activation of kinases, like AMP-activated protein kinase (AMPK) and ULK1. Although glucose starvation induces autophagy, the exact mechanism underlying this signaling has yet to be elucidated. Here, we reveal a role for ULK1 in non-canonical autophagy signaling using diverse cell lines. ULK1 activated by AMPK during glucose starvation phosphorylates the lipid kinase PIKfyve on S1548, thereby increasing its activity and the synthesis of the phospholipid PI(5)P without changing the levels of PI(3,5)P-2. ULK1-mediated activation of PIKfyve enhances the formation of PI(5)P-containing autophagosomes upon glucose starvation, resulting in an increase in autophagy flux. Phospho-mimic PIKfyve S1548D drives autophagy upregulation and lowers autophagy substrate levels. Our study has identified how ULK1 upregulates autophagy upon glucose starvation and induces the formation of PI(5)P-containing autophagosomes by activating PIKfyve.
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