Mechanisms controlling amino acid signaling to mTOR and lysosome fission.

描述（由申请人提供）：细胞吞噬机制的终末阶段是吞噬作用和内吞作用（介导外源底物的摄取），以及自噬作用（介导细胞内底物的吞噬），涉及吞噬货物的溶酶体消化和钙转运蛋白输出至胞质溶胶用于生物合成。尽管这些途径对于去除靶向底物具有关键作用，并且溶酶体介导的消化对于吞噬物质的实际清除和再循环具有重要性，但关于如何调节吞噬货物的溶酶体加工和降解组分的输出知之甚少。我们已经发现，mTOR蛋白激酶是mRNA翻译和自噬的调节剂，是吞噬体分裂程序所必需的，该程序随着内化的货物被降解而收缩大的溶酶体空泡，这让人想起最近描述的自噬溶酶体重组（ALR）程序，其在自噬过程中起类似的作用。mTORC1通过从吞噬细胞中回收氨基酸而被激活，并特异性地募集到容纳降解细胞的大溶酶体空泡中以控制其分裂。拟议的研究将确定在溶酶体中作用的介导氨基酸恢复和mTORC 1激活的氨基酸转运蛋白，并将确定控制溶酶体空泡分裂的mTOR调节蛋白。

DESCRIPTION (provided by applicant): The end stages of the cellular engulfment mechanisms phagocytosis and entosis, which mediate the uptake of exogenous substrates, and autophagy, which mediates the engulfment of intracellular substrates, involve lysosomal digestion of engulfed cargo and export of catabolites to the cytosol for use in biosynthesis. Despite the critical role of these pathways for the removal of targeted substrates, and the importance lysosome- mediated digestion for the actual clearance and recycling of engulfed material, little is known about how the lysosomal processing of engulfed cargo and export of degraded components is regulated. We have found that the mTOR protein kinase, a regulator of mRNA translation and autophagy, is required for a program of phagosome fission that shrinks large lysosomal vacuoles as internalized cargo is degraded, which reminiscent of the recently described autophagic lysosome reformation (ALR) program that functions similarly during autophagy. mTORC1 is activated by amino acid recovery from engulfed cells, and is recruited specifically to large lysosomal vacuoles harboring degrading cells to control their fission. The proposed research will identify amino acid transporters acting at lysosomes that mediate amino acid recovery and mTORC1 activation, and will identify mTOR-regulated proteins that control the fission of lysosomal vacuoles.