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 Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/11127

 Title: Membrane Surface Charge and Lipid Signaling in Phagocytosis Authors: Yeung, Tony Advisor: Grinstein, Sergio Department: Medical Science Keywords: cell biology Issue Date: 28-Jul-2008 Abstract: Phagocytosis is an important component of innate and adaptive immunity. The formation of phagosomes and the subsequent maturation that capacitates them for pathogen elimination and antigen presentation are complex processes that involve signal transduction, cytoskeletal reorganization and membrane remodeling. Lipids are increasingly appreciated to play a crucial role in these events. Sphingolipids, cholesterol and glycerophospholipids, notably the phosphoinositides, are required for the segregation of signaling microdomains and for the generation of second messengers. They are also instrumental in the remodeling of the actin cytoskeleton and in directing membrane traffic. They accomplish these feats by congregating into liquid-ordered domains, by generating active metabolites that activate receptors and by recruiting and anchoring specific protein ligands to the membrane, often altering their conformation and catalytic activity. A less appreciated role of acidic phospholipids is their contribution to the negative surface charge of the inner leaflet of the plasmalemma. The unique negativity of the inner aspect of the plasma membrane serves to attract and anchor key signaling and effector molecules that are required to initiate phagosome formation. Conversely, the loss of charge that accompanies phospholipid metabolism as phagosomes seal facilitates the dissociation of proteins and the termination of signaling and cytoskeleton assembly. In this manner, lipids provide a binary electrostatic switch to control phagocytosis. Phosphatidylserine, an abundant but relatively little studied anionic phospholipid, is expected to contribute significantly to the surface charge of membranes. The development of a PS-specific biosensor revealed that this lipid is distributed to the cytosolic leaflet of the plasma membrane and of the membranes of the endocytic pathway. Consequently, the charge conferred by PS directs the targeting of proteins with cationic domains or polybasic clusters to these membrane compartments. PS is also present on the phagosome membrane and similarly helps to recruit cationic proteins to this organelle. The electrostatic switch theory as proposed by McLaughlin and Aderem provides a novel biophysical mechanism in which proteins can be regulated in cells, in parallel with the traditional biochemical mechanisms that regulate the activity and conformational status of proteins. URI: http://hdl.handle.net/1807/11127 Appears in Collections: DoctoralInstitute of Medical Science - Doctoral theses

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