The RNA binding protein IMP1/ZBP1 drives mRNA local translation in microglia and mediates polarized migration and phagocytosis in response to inflammation

Abstract

ABSTRACTPolarized cells in the brain, such as neurons and glia, rely on the asymmetric distribution of their proteins compartmentalizing the function of dendrites, axons, glial projections and endfeet. Subcellular proteomes can be assembled either by the transport of proteins synthesized in the cell soma or by the delivery of mRNAs to target compartments where they are locally translated into protein. This latter mechanism is known as local protein synthesis or local translation, and it has been best studied in neurons. Increasing evidence suggest it is also required to maintain local protein homeostasis in glial cells, however, in microglia, local translation remains largely unexplored. Given the scant evidence, we aimed at exploring the existence of local translation in microglial peripheral processes (MPPs) and unravel its functional significance. We report that local translation indeed happens in MPPs and it is enhanced by triggering a microglial inflammatory response with bacterial lipopolysaccharides (LPS) suggesting a functional relevance of this molecular mechanism in response to inflammation. We found thatActbandPar3mRNAs polarize to MMPs and are locally translated upon LPS exposure. Interestingly, downregulation of theActbbinding protein IMP1/ZBP1 impairedActbmRNA polarization and its localized translation, leading to defects in filopodia distribution, lamellar directed migration and phagocytosis in microglia. Thus, our work contributes to recent findings that localized translation occurs in microglia and gives a mechanistic insight into the relevance of this molecular mechanism in fundamental microglial functions in response to LPS-induced inflammation.