The actin cytoskeleton has many essential functions. Actin polymerization drives membrane movements, and actin filaments assemble into a scaffold that supports the cells’ motors and signaling machinery. The scaffold is continually remodeled in proliferating cells, and is completely dismantled in apoptotic cells. We are studying how phosphatidylinositol 4,5 bisphosphate (PIP2), a membrane lipid, regulates the actin scaffold in proliferating and apoptotic cells.
We focus on the lipid kinases that synthesize PIP2 (phosphatidylinositol phosphate 5 kinases, PIP5Ks) and PI4P (phosphatidylinositol 4 kinases, PI4Ks), as well as the regulatory proteins that respond to PIP2 and PI4P.
The 3’-phosphoinositides PI3P and PI(3,4,5)P3 have been established as key regulators of autophagy and cell survival. We recently discovered that the 4’-phosphoinositide, PI4P, which is the gatekeeper to the canonical PIP2 and PIP3 signaling pathways, has a pivotal role in its own right in directly regulating autophagosome:lysosome fusion at the final and critical step in the autophagic process.
This PI4P is generated exclusively by the type II phosphatidylinositol 4-kinase IIα (PI4KIIα), which is concentrated in the Golgi region in growing cells. PI4KIIα translocates to the autophagosomes in a GABARAP-dependent manner. Since GABARAP is a much less understood autophagy-related family protein than LC3, and PI4KIIα binds GABARAP but not LC3, we propose that PI4KIIα is a GABARAP effector in autophagosome maturation and fusion.
Our goal is to follow up on these novel findings to determine how the GABARAP/PI4KIIα/PI4P interaction regulates autophagosome:lysosome fusion at this critical stage of autophagy.