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Mariella Vicinanza, Ph.D - "Phosphoinositides and autophagosome biogenesis"

Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK
When Apr 13, 2017
from 12:00 PM to 01:30 PM
Where tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Short CV

Phosphoinositides are phosphorylated derivatives of phosphatidylinositol involved in controlling the cytosol–membrane interface of most subcellular compartments. When clustered, PIs create a cytosol-facing platform enabling the binding of machineries that regulate membrane trafficking, signalling and cytoskeletal remodelling. The combined activities of multiple phosphoinositide kinases and phosphatases enable inter-convertibility and rapid local changes of PI concentrations.
Phosphatidylinositol 3-phosphate (PI(3)P), the product of class III PI3K VPS34, recruits specific autophagic effectors, like DFCP1 (double FYVE-containing protein 1) and WIPI2, (WD-repeat protein interacting with phosphoinositide), during the initial steps of autophagosome biogenesis and thereby regulates canonical autophagy. However, mammalian cells can produce autophagosomes through enigmatic non-canonical VPS34-independent pathways. These phenomena may be explicable by VPS34-independent source(s) of PI(3)P, or by other phosphoinositides having similar properties to PI(3)P in the autophagy context.
The structure of PI(3)P is related by rotation to that of Phosphatidylinositol 5-phosphate (PI(5)P). PI(5)P has been previously implicated in growth factor signalling pathways, chromatin organization, bacterial invasion and cytoskeletal remodelling and we provided the first report for PI(5)P as an autophagy regulator. We found that (PI(5)P) can regulate autophagy via PI(3)P effectors, and thereby identify a mechanistic explanation for forms of non-canonical autophagy. PI(5)P synthesis by the phosphatidylinositol 5-kinase PIKfyve was required for autophagosome biogenesis and increased levels of PI(5)P stimulated autophagy and reduced the levels of autophagic substrates. Inactivation of VPS34 impaired recruitment of WIPI2 and DFCP1 to autophagic precursors, reduced ATG5-12 conjugation and compromised autophagosome formation. However, these phenotypes were rescued by PI(5)P in VPS34-inactivated cells. These findings provide a mechanistic framework for alternative VPS34-independent autophagy-initiating pathways, like glucose starvation, and unravel a novel cytoplasmic function for PI(5)P, which has previously been linked predominantly to signalling, cytoskeleton remodelling and nuclear roles.

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