Nutrient transport, membrane trfficking, and mTORC1 signaling at lysosomes.

溶酶体的营养转运、膜转运和 mTORC1 信号传导。

基本信息

批准号：
8919927
负责人：
Michael H. Overholtzer
金额：
$ 34.78万
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：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8919927
关键词：
Amino Acid Transport System A Amino Acid Transporter Amino Acids Amino Sugars Anabolism Autophagocytosis Breast Carcinoma Cell Culture Techniques Cell Proliferation Cell Survival Cells Colon Carcinoma Complex Cytosol Data Digestion Excision Genetic Translation Glucose Glucose Transporter Growth Factor Health Homeostasis Human Life Lipids Lysosomes Malignant Neoplasms Mediating Mediator of activation protein Membrane Membrane Protein Traffic Modeling Nutrient Pathway interactions Phagocytes Phagocytosis Phagosomes Phosphorylation Phosphotransferases Process Protein Kinase Proteins Proteomics Pyruvate Recovery Recruitment Activity Recycling Regulation Reporting Research Role Signal Pathway Signal Transduction Source Stable Isotope Labeling Staging Starvation System Therapeutic Transmembrane Transport Vacuole base human FRAP1 protein leukemia loss of function lung Carcinoma lysosome membrane mTOR protein macrophage novel programs research study sugar 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 mTORC1 protein kinase, a regulator of mRNA translation and autophagy, and the lipid kinase PIKfyve, are 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. Vacuole fission is associated with nutrient recovery that rescues engulfing cells from the effects of amino acid or glucose/pyruvate starvation, and reactivates mTORC1. Reactivated mTOR recruits specifically to large lysosomal vacuoles harboring degrading cells and controls their fission. The proposed research will identify amino acid and sugar transporters acting at lysosomes that mediate nutrient recovery and mTORC1 activation, and will identify mTOR and PIKfyve-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，MTORC1蛋白激酶是mRNA翻译和自噬的调节剂，以及脂质激酶pikfyve需要的吞噬体裂变程序需要将大型溶酶体吸尘器作为内在化货物的缩小降解，这是在最近描述的自动元素重新构造（Aliphapic Replorys）的情况下，将其缩减为内部化的货物。液泡裂变与营养恢复有关，从而从氨基酸或葡萄糖/丙酮酸饥饿的作用中挽救了吞噬细胞，并重新激活了MTORC1。重新激活了MTOR招募，专门针对具有降解细胞并控制其裂变的大型溶酶体液泡。拟议的研究将确定作用于介导营养恢复和MTORC1激活的溶酶体作用的氨基酸和糖转运蛋白，并将鉴定控制MTOR和PIKFYVE调节的蛋白质，以控制溶酶体液泡的裂变。