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。

基本信息

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
项目类别：
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

项目摘要

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）：细胞吞噬机制的终点吞噬和诱惑，介导了外源性底物的摄取，以及自噬，介导了吞噬细胞内底物的吞噬，涉及吞噬货物的溶酶体对catos catos and catosos in Cytosol in Cytosol cytosol in Cytosol cytosol cytosol cytosol cytosol cytosol cytosol cytosol in cytosol in Cytosol。尽管这些途径在去除靶向底物方面的作用至关重要，以及对吞噬材料的实际清除和回收的溶酶体介导的消化的重要性，但对吞噬货物的溶酶体处理以及降级成分的出口的溶酶体处理如何受到调节。我们发现，MTOR蛋白激酶是mRNA翻译和自噬的调节剂，是吞噬体裂变程序所必需的，该程序将大量的溶酶体液泡缩小为内部化货物的降解，这让人想起最近描述的自噬溶酶体改革（ALR）程序，该程序在自动上类似。 MTORC1通过氨基酸从吞噬细胞中恢复而激活，并专门募集到具有降解细胞以控制其裂变的大型溶酶体液泡中。拟议的研究将确定作用于介导氨基酸回收和MTORC1激活的溶酶体的氨基酸转运蛋白，并将鉴定控制MTOR调节的蛋白，以控制溶酶体液泡的裂变。