ANALYSIS OF ESCRT FUNCTION IN ENDOLYSOSOMAL TRAFFICKING

内溶酶体转运中 ESCRT 功能的分析

基本信息

批准号：
10798848
负责人：
Phyllis I Hanson
金额：
$ 11.46万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2025-07-31
项目状态：
未结题

项目摘要

Abstract The endolysosomal network is the portal by which extracellular material enters the cell. As such, the membranes of the endosomes, phagosomes, and lysosomes that comprise this network face challenges from pathogens and other internalized materials as well as from metabolic and chemical stresses. Consequences of damage vary according to the specific compartment and degree of damage, but extensive lysosomal membrane permeabilization triggers cell death while limited disruption of endosomes and phagosomes by particulate material and pathogens leads to inflammasome activation and ensuing cytokine responses. A widely deployed strategy for removing damaged organelles involves the use of selective autophagy, referred to as lysophagy. Removal is, however, unnecessary if organelles are instead repaired. We recently discovered a new role for the ESCRT (endosomal sorting complex required for transport) machinery in responding to nano- scale disruptions in endolysosomal membranes and promoting their repair. In this project, we are building on this discovery and testing the hypothesis that ESCRTs (and in particular ESCRT-III proteins) play a key role in maintaining endolysosomal integrity and function by recognizing and repairing nanoscale membrane damage. This role for the ESCRT machinery is distinct from its widely recognized function in intralumenal vesicle biogenesis and appears applicable at both the plasma membrane and on internal organelles. Nanoscale damage involves short-lived nm-size pre-pore or pore(s) that reseal or, above a critical threshold, expand to allow unrestrained content exchange. We are using a range of chemical, physical, and biological stressors to define the signals as well as molecular and physical mechanisms underlying ESCRT-mediated repair. The Tecan Spark multimode plate reader requested in this administrative supplement application will allow us to move our assays of endolysosomal membrane stress and organelle resilience from our current low-throughput to a high-throughput format, thereby providing the rigorous and quantitative assessment of endolysosomal resilience to different pharmacologic and genetic stressors needed to complete this project and provide insight into how cells respond to a broad range of physiologic and pathophysiologic membrane stress.

抽象的内溶性网络是细胞外材料进入细胞的门户网站。因此，构成该网络的内体，吞噬体和溶酶体的膜面临挑战病原体和其他内部材料以及代谢和化学应力。后果损害因特定隔室和损害程度而异，但溶酶体广泛膜通透性触发细胞死亡，而受限的内体和吞噬体有限。颗粒物质和病原体会导致炎症体激活并随后的细胞因子反应。一个去除受损细胞器的广泛部署的策略涉及选择性自噬的使用，作为溶物。但是，如果细胞器要修复，则去除是不必要的。我们最近发现了一个 ESCRT（运输所需的内体分类复合物）机械的新作用在响应纳米内侧溶性膜的尺度破坏并促进其修复。在这个项目中，我们正在基于这一发现并检验ESCRT的假设（尤其是 ESCRT-III蛋白）通过识别和修复纳米级膜损伤。 ESCRT机械的这一角色与其广泛不同公认的功能在赤囊囊泡生物发生中，并且似乎适用于两种质膜以及内部细胞器。纳米级损害涉及重新密封或，，，在关键阈值之上，扩展以允许不受限制的内容交换。我们正在使用一系列化学物质物理和生物压力源以定义信号以及分子和物理机制基础ESCRT介导的修复。 Tecan Spark Multimode Plate读取器在此管理中要求补充应用将使我们能够移动内溶性膜膜压力和细胞器的测定法从当前的低通量到高通量格式的弹性，从而提供了严格的和对所需的不同药理和遗传应激源的内溶性弹性的定量评估完成该项目并提供有关细胞如何响应各种生理和病理生理膜应激。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Triggered recruitment of ESCRT machinery promotes endolysosomal repair.

DOI：
10.1126/science.aar5078
发表时间：
2018-04-06
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Skowyra ML;Schlesinger PH;Naismith TV;Hanson PI
通讯作者：
Hanson PI

Mycobacterium tuberculosis Type VII Secretion System Effectors Differentially Impact the ESCRT Endomembrane Damage Response.

DOI：
10.1128/mbio.01765-18
发表时间：
2018-11-27
期刊：
mBio
影响因子：
6.4
作者：
Mittal E;Skowyra ML;Uwase G;Tinaztepe E;Mehra A;Köster S;Hanson PI;Philips JA
通讯作者：
Philips JA

Mechanism and cellular function of direct membrane binding by the ESCRT and ERES-associated Ca2+-sensor ALG-2.

ESCRT 和 ERES 相关 Ca2 传感器 ALG-2 直接膜结合的机制和细胞功能。

DOI：
10.1101/2023.10.17.562764
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Shukla,Sankalp;Chen,Wei;Rao,Shanlin;Yang,Serim;Ou,Chenxi;Larsen,KevinP;Hummer,Gerhard;Hanson,PhyllisI;Hurley,JamesH
通讯作者：
Hurley,JamesH

ESCRT puts its thumb on the nanoscale: Fixing tiny holes in endolysosomes.