A study on non-canonical autophagy signalling

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An essential requirement for cell viability is the ability to restore energy supplies to avoid exhaustion of all resources upon nutrient depletion. Autophagy is an essential catabolic process induced to provide cellular energy sources in response to nutrient limitation through the engulfment of intracellular content in double-membrane vesicles known as autophagosomes, which fuse with lysosomes for the degradation and recycling of the autophagic cargo. Nutrient starvation leads to the induction of autophagy by activating the master regulator AMP-activated protein kinase (AMPK). AMPK activates multiple downstream regulators such as ULK1, which in the canonical pathway is known to activate the VPS34 complex, resulting in the formation of PI(3)P-containing autophagosomes. A failure to induce functional autophagy has been implicated in a range of neurodegenerative diseases, in which the aggregation of toxic proteins and organelles cause neuronal loss. Since studies suggest that canonical PI(3)P-dependent autophagy is impaired in many neurodegenerative diseases, the potential of upregulating non-canonical autophagy holds great therapeutic value. As earlier research showed that autophagy can be upregulated in a VPS34-independent, PI(5)P-dependent manner upon glucose starvation, in this thesis I elucidated the mechanism leading to upregulation of PI(5)P-dependent autophagy. Here, a new role has been revealed for ULK1. ULK1 activated by AMPK during glucose starvation phosphorylates the lipid kinase PIKfyve on amino acid S1548, thereby increasing its kinase activity and the synthesis of the phospholipid PI(5)P without changing the levels of PI(3,5)P2. 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 such as the neurodegeneration-associated mutant polyQ-huntingtin. This study has identified how ULK1 upregulates autophagy upon glucose starvation and induces the formation of PI(5)P-containing autophagosomes by activating PIKfyve, revealing a novel mechanism by which autophagy is induced.

Rubinsztein, David
autophagy, cell biology, signalling, ulk1, ampk, PIKfyve, phospholipids
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
Gates Cambridge Scholarship