Regulation of phosphoinositide lipid signalling and its function in determining organelle identity

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From yeast to human, eukaryotic cells are characterized by membrane-bound compartments called organelles. There are many organelle types, each with distinct biophysical, biochemical and functional properties. For example, the endoplasmic reticulum is a labyrinth of membrane tubules where lipid and protein synthesis occurs while lysosomes are small, round organelles full of digestive enzymes. Interestingly, organelles relentlessly exchange content. Therefore, a very important question for cell biologists is how do cells establish and maintain the various types of organelles - in other words, what determines organelle identity? The phosphoinositide (PtdInsP) signalling phospholipids are key determinants of organelle identity. There are seven PtdInsPs, each exhibiting a stereotypical intracellular distribution and levels. A specific PtdInsP binds and recruits cognate protein effectors to a membrane, which then endows that membrane with a specific function. In order to understand how PtdInsPs help to determine organelle identity, cell biologists need to understand both how the enzymes that synthesize and degrade PtdInsPs are properly targeted and coordinated as well as how PtdInsP effector proteins work. My laboratory seeks to understand these questions to improve our understanding of how cells function within our bodies. Here, I propose to study a specific PtdInsP, phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2], which controls the morphology and membrane traffic of organelles in the late endocytic pathway. The Vac14 adaptor protein is a scaffolding protein that interacts with itself and four other PI(3,5)P2 regulators including the Fab1 kinase and the Fig4 phosphatase that synthesizes and degrades PI(3,5)P2, respectively (Botelho et al. 2008). The current proposal seeks to improve our understanding of how Vac14 interfaces with these other proteins to govern PI(3,5)P2. This is important since PI(3,5)P2 misregulation is associated with neurodegeneration and is linked to glucose uptake. This proposal may provide the Canadian biopharmaceutical industry with novel strategies to ameliorate conditions caused by PtdInsP malfunction and decrease its the negative impact on affected Canadians and the Canadian economy.