Illuminating Organellar and Molecular Organization of the Endomembrane System




Hsieh, Ting-Sung

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The endomembrane system consists of virtually all of the structurally and functionally distinct membrane compartments in a eukaryotic cell, except mitochondria and plastids. Different compartments in the endomembrane system communicate with each other through vesicular transport as well as direct membrane-membrane contact. In this work, I first probe spatial organization of membrane contact sites between the endoplasmic reticulum and the plasma membrane in mammalian cells. These membrane contact sites, termed endoplasmic reticulum-plasma membrane junctions, mediate cellular activities ranging from Ca2+ signaling to lipid metabolism. I provide quantitative information on spatial organization of endoplasmic reticulum-plasma membrane junctions and show that it is in part regulated by F-actin. This gives clues about how cellular activities of endoplasmic reticulum-plasma membrane junctions may be regulated because their spatial organization dictates the extent and location of these cellular activities. Then, I examine the phosphoinositide identities of mammalian late endocytic compartments. Phosphoinositides perform the pivotal role as identifiers for different membrane compartments. I show that phosphatidylinositol 3-phosphate is presnt on late endosomes while phosphatidylinositol 4-phosphate is presnt on some endolysosomes and lysosomes. This yields clues about how phosphoinositides regulate membrane sorting and biogenesis of different late endocytic compartments. Last, I show the alteration of phosphoinositide identity of the endoplasmic reticulum by the phosphatidylinositol 3-kinase MavQ secreted by Legionella pneumophila. L. pneumophila exploits the host endoplasmic reticulum membrane to form a Legionella-containing vacuole for intracellular replication. I reveal that MavQ generates phosphatidylinositol 3-phosphate on the endoplasmic reticulum membrane and that MavQ, together with the phosphatidylinositol 3-phosphatase SidP, self-organizes and propagates on the endoplasmic reticulum membrane in a wave-like manner and drives vesicle/tubule generation along the way. This not only provides insight into how L. pneumophila subverts the host cell to establish their own niche but also highlights the importance of concerted kinase/phosphatase integration in generating complex cellular behaviors.

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