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

Abstract

Polarized 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 peripheral microglial processes (PeMPs) and unravel its functional significance in response to inflammation, a major hallmark of neurodegenerative diseases. We report that local translation in PeMPs is enhanced by triggering a microglial inflammatory response with bacterial lipopolysaccharides (LPS). We found that Actb mRNA polarizes to PeMPs and is locally translated upon LPS exposure. mRNA localization in eukaryotic cells is driven by RNA binding proteins. Interestingly, downregulation of the Actb binding protein IMP1/ZBP1 impaired Actb mRNA polarization and its localized translation, and led to defects in filopodia distribution, PeMP motility, lamellar directed migration and phagocytosis in microglia. Thus, our work contributes to recent findings that mRNA localization and localized translation occur in microglia and gives a mechanistic insight into the relevance of this molecular mechanism in fundamental microglial functions in response to inflammation.