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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.

摘要

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

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

DOI：
10.1016/j.ceb.2020.06.002
发表时间：
2020-08
期刊：
Current opinion in cell biology
影响因子：
7.5
作者：
Bohannon KP;Hanson PI
通讯作者：
Hanson PI

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