Mechanisms controlling amino acid signaling to mTOR and lysosome fission.

控制 mTOR 氨基酸信号传导和溶酶体裂变的机制。

• 批准号: 8559677
• 负责人: Michael H. Overholtzer
• 金额: $ 23.07万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8559677
• 关键词: Adaptor Signaling Protein; Amino Acid Transporter; Amino Acids; Anabolism; Autophagocytosis; Breast Carcinoma; Cell Culture Techniques; Cells; Clathrin; Clathrin Adaptors; Colon Carcinoma; Complex; Cytosol; Digestion; Enzymes; Excision; Genetic Translation; Growth Factor; Human; Life; Lipids; Lysosomes; Malignant Neoplasms; Mammalian Cell; Mediating; Membrane; Modeling; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Process; Protein Kinase; Proteins; Proteomics; Recovery; Recruitment Activity; Recycling; Regulation; Reporting; Research; Role; Signal Transduction; Source; Stable Isotope Labeling; Staging; System; Therapeutic; Vacuole; base; human FRAP1 protein; inhibitor/antagonist; inorganic phosphate; leukemia; loss of function; lung Carcinoma; lysosomal proteins; lysosome membrane; mTOR protein; macrophage; novel; programs; public health relevance; research study; therapeutic target; uptake

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.

描述（由申请人提供）：细胞吞噬机制的最后阶段吞噬和内吞，介导外源底物的摄取，以及自噬，介导细胞内底物的吞噬，包括溶酶体消化吞噬的货物，并将分解代谢物出口到细胞质中用于生物合成。尽管这些途径在清除目标底物中起着关键作用，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也很重要，但对于吞噬货物的溶酶体加工和降解成分的出口是如何被调节的，我们知之甚少。我们发现，mRNA翻译和自噬的调节因子mTOR蛋白激酶是吞噬体分裂程序所必需的，当内化货物被降解时，吞噬体分裂程序会收缩大的溶酶体液泡，这让人想起最近描述的自噬溶酶体重组（ALR）程序，它在自噬过程中具有类似的功能。mTORC1被吞噬细胞的氨基酸回收激活，并被特异性地招募到容纳降解细胞的大溶酶体液泡中，以控制它们的裂变。拟议的研究将确定作用于溶酶体的氨基酸转运体，介导氨基酸恢复和mTORC1激活，并将确定控制溶酶体空泡裂变的mtor调节蛋白。