RNA binding protein IMP1/ZBP1 drives mRNA localization and local translation in microglial peripheral processes and mediates morphological changes, motility and phagocytosis in response to inflammation.

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 microglial peripheral processes (PeMPs) and unravel its functional significance. We report that local translation indeed happens in PeMPs 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 that Actb mRNA polarizes to PeMPs and is locally translated upon LPS exposure. 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.大脑中的极化细胞（polarized cells），例如神经元（neurons）与胶质细胞（glia），依赖蛋白质的不对称分布来实现树突（dendrites）、轴突（axons）、胶质突起（glial projections）及终足（endfeet）的功能区室化。亚细胞蛋白质组（subcellular proteomes）的组装可通过两种途径实现：一是转运在细胞胞体（cell soma）中合成的蛋白质，二是将信使RNA（mRNAs）递送至靶区室，在该处完成局部蛋白质翻译。后者被称为局部蛋白质合成（local protein synthesis）或局部翻译（local translation），该机制在神经元中的研究最为深入。越来越多的证据表明，该机制对于维持胶质细胞的局部蛋白质稳态（protein homeostasis）同样不可或缺，然而在小胶质细胞（microglia）中，局部翻译的相关研究仍未得到充分探索。鉴于相关研究证据匮乏，本研究旨在探究小胶质细胞外周突起（microglial peripheral processes, PeMPs）中局部翻译的存在性，并阐明其功能意义。本研究证实，局部翻译确实存在于小胶质细胞外周突起中，且细菌脂多糖（bacterial lipopolysaccharides, LPS）诱导小胶质细胞炎症反应时，该过程会被增强，这提示该分子机制在炎症应答中具有功能相关性。研究发现，肌动蛋白βmRNA（Actb mRNA）会极化至小胶质细胞外周突起，并在脂多糖暴露时发生局部翻译。值得注意的是，下调肌动蛋白βmRNA结合蛋白IMP1/ZBP1会削弱Actb mRNA的极化及其局部翻译过程，并导致小胶质细胞出现丝状伪足（filopodia）分布异常、小胶质细胞外周突起运动障碍、片状定向迁移缺陷以及吞噬作用（phagocytosis）受损等表型。综上，本研究为“小胶质细胞中存在mRNA定位与局部翻译”这一近年研究成果提供了新的支撑，并为该分子机制在小胶质细胞响应炎症的核心生理功能中的相关性提供了机制层面的深入见解。