Regulation and Function of Phosphoinositide Lipid Signalling

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Membrane-bound organelles are the "organs" of cells. 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 protein synthesis occurs, whereas lysosomes are small, round organelles full of digestive enzymes. How organelles form or change is a central question in cell biology. ******The phosphoinositide (PIP) lipids are architects of organelle identity. There are seven PIP species that are differentially distributed among organelles. Since each PIP species binds and recruits a unique set of proteins, then this decorates the host organelle with a unique set of molecular properties. In order to understand how PIPs help to determine organelle identity, cell biologists need to understand A) how the enzymes that synthesize and degrade PIPs are targeted and regulated and B) how PIPs and their effector proteins work. ******Here, I propose to study a specific PIP, phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2], which controls the morphology and membrane traffic of organelles in the endocytic pathway. This pathway is responsible for sorting and trafficking proteins to various destinations including the cell surface or for degradation in lysosomes. It also interfaces with the phagocytic pathway, which immune cells use to destroy pathogens. With NSERC support:******i) We will study the role of PI(3,5)P2 and its effectors in macrophages and neutrophils. These immune cells hunt and engulf pathogens into phagosomes to digest and kill them. We have previously showed that phagosomes require PI(3,5)P2 to become degradative in macrophages. The new research will seek to understand how PI(3,5)P2 is important for phagosome maturation and explore its role in neutrophils, the first responders to an infection. ******ii) We will perform unprecedented studies to understand how PI(3,5)p2 controls lysosome size by following the dynamics, kinetics and mechanisms by which PI(3,5)P2 depletion causes massive lysosome swelling. This dramatic change to lysosomes remains poorly uncharacterized. ******iii) We will study the origin and functions of two different pools of PI(3)P in cells. PI(3)P is the precursor for PI(3,5)P2, but it is unclear when and where this conversion occurs. Using cutting-edge research and genetic engineering, we will aim to better understand how individual pools of PI(3)P function, which will then inform us about the transition of PI(3)P to PI(3,5)P2.******Overall, my research will answer questions in cell biology related to PIP regulation and function. These answers may then have implications for organismal well-being since PI(3,5)P2 dysfunction causes neurodegeneration and may disrupt the immune response. Our findings may provide the Canadian biotechnology and pharmaceutical industries with novel strategies to treat conditions caused by PIP malfunction that afflicts Canadians.**