Shen Kimberle, Sidik Harwin, Talbot William S
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Rep. 2016 Jan 26;14(3):547-559. doi: 10.1016/j.celrep.2015.12.055. Epub 2016 Jan 7.
Microglia are resident macrophages of the CNS that are essential for phagocytosis of apoptotic neurons and weak synapses during development. We show that RagA and Lamtor4, two components of the Rag-Ragulator complex, are essential regulators of lysosomes in microglia. In zebrafish lacking RagA function, microglia exhibit an expanded lysosomal compartment, but they are unable to properly digest apoptotic neuronal debris. Previous biochemical studies have placed the Rag-Ragulator complex upstream of mTORC1 activation in response to cellular nutrient availability. Nonetheless, RagA and mTOR mutant zebrafish have distinct phenotypes, indicating that the Rag-Ragulator complex has functions independent of mTOR signaling. Our analysis reveals an essential role of the Rag-Ragulator complex in proper lysosome function and phagocytic flux in microglia.
小胶质细胞是中枢神经系统中的常驻巨噬细胞,在发育过程中对凋亡神经元和薄弱突触的吞噬作用至关重要。我们发现,Rag-Ragulator复合物的两个组成部分RagA和Lamtor4是小胶质细胞中溶酶体的关键调节因子。在缺乏RagA功能的斑马鱼中,小胶质细胞表现出溶酶体区室扩大,但它们无法正常消化凋亡神经元碎片。先前的生化研究表明,Rag-Ragulator复合物在响应细胞营养可用性时位于mTORC1激活的上游。尽管如此,RagA和mTOR突变斑马鱼具有不同的表型,这表明Rag-Ragulator复合物具有独立于mTOR信号传导的功能。我们的分析揭示了Rag-Ragulator复合物在小胶质细胞中溶酶体正常功能和吞噬通量中的重要作用。