Understanding fish immune receptor-mediated control of the phagocytic process

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Phagocytosis is an innate cellular immune defense response that involves the recognition, engulfment, and eventual destruction of extracellular targets such as bacteria. An important mechanism of immunity in all animals, phagocytosis has evolved from a primitive nutrient acquisition process by unicellular organisms into a fundamental innate defense and homeostatic processes in all complex multicellular animals. Cells that perform phagocytosis are called phagocytes and the activity of these specialized cells is dependent upon their expression of specific cell-surface proteins. These proteins bind targets and then trigger signaling cascades that activate actin-dependent membrane remodeling events required for the active capture and engulfment of targets. Each phagocytic receptor exists as a cell-surface protein containing an extracellular region, providing the interface for target recognition, as well as an intracellular cytoplasmic tail that is responsible for triggering the subcellular signaling events that couple to the actin cytoskeleton. Despite an understanding of phagocytic mechanisms in mammals, very little is known about this important immune response in other animals. The lack of information on such a primitive defense strategy is an obvious gap that can be filled using basal vertebrate immune models such as fish. Recently, our work has shown that certain fish immune proteins can control phagocytosis via mechanisms that are conserved with the prototypical mammalian pathways. However, one of these fish immune receptor-types was also shown to activate phagocytosis using a completely novel mechanism. We also demonstrated that this unique phagocytic pathway in fish was uniquely associated with the generation of plasma membrane-derived protrusions that actively participated in the capture of extracellular targets. A fluorescent reporter that tracks F-actin dynamics in live cells revealed that the formation of these cellular protrusions also required atypical patterns of actin polymerization. These findings suggest, for the first time, that a specific teleost receptor-mediated pathway can selectively control the formation of plasma membrane protrusions. Such actin-dependent membranous extensions, more commonly called filopodia or cellular tentacles, have been implicated in the regulation of numerous biological processes, including cell adhesion, cell migration, as well tumor invasiveness. That said, our knowledge of the receptors and molecular mechanisms that contribute to the spatiotemporal dynamics of filopodia formation are very limited. Our proposed studies will contribute specific new details into immunoregulatory receptor signaling events during phagocytosis and, more generally, towards understanding the dynamic membrane remodeling events that are associated with other fundamental cellular processes, including filopodia production.