Mechanisms of Endosomal Sorting

内体分选机制

基本信息

批准号：
8473224
负责人：
DAVID J KATZMANN
金额：
$ 31.79万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8473224
关键词：
ATP Hydrolysis ATP phosphohydrolase Animal Model Atherosclerosis Biochemical Cell Surface Proteins Cell membrane Cell physiology Complement Complex Cues Cytokinesis Cytoplasm Defect Development Dissociation Endocytosis Environment Epithelial Excision Failure Functional disorder Growth Factor Receptors HIV-1 Homeostasis Hypertension Individual Inherited Integral Membrane Protein Lead Link Lysosomes Mediating Membrane Multivesicular Body Neurodegenerative Disorders Organism Pathway interactions Plants Process Proteins Reaction Regulation Reproduction Role Saccharomyces cerevisiae Signal Transduction Sodium Channel Sorting - Cell Movement Specific qualifier value Staging Sum Syndrome Vesicle Viral Virus Yeasts cancer prevention cohort constriction endosome lumen human disease in vivo insight lipid transport man public health relevance receptor receptor downregulation response tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Multivesicular body (MVB) sorting is a critical process within the endocytic pathway wherein portions of the endosomal membrane bud into the endosomal lumen. Failure to target activated growth factor receptors into the MVB pathway results in prolonged signaling that can contribute to tumorigenesis and defects in organism development. Defects in MVB targeting of the epithelial sodium channel result in an inherited form of hypertension (Liddle's syndrome). Neurodegenerative diseases have been linked to dysfunction of the MVB pathway, and aberrant trafficking of lipids through this pathway also contributes to a number of human disease states, including atherosclerosis. MVB sorting is mediated by the endosomal sorting complexes required for transport (ESCRT-0, I, II, and III) and associated factors including the AAA-ATPase Vps4. In addition to roles in MVB sorting, the ESCRTs and Vps4 are usurped by enveloped viruses (e.g. HIV-1 and Ebola) to execute their cellular egress. Furthermore, the ESCRTs and Vps4 contribute to membrane abscission during cytokinesis. These examples highlight numerous processes impacted by ESCRT function as well as maladies that arise upon dysfunction. Vps4 and ESCRT-III act in a coordinated manner during membrane deformations of similar topology (away from the cytoplasm) that occur in MVB sorting, viral budding, and membrane abscission. Dissociation of ESCRT-III through Vps4 ATP hydrolysis is required for these processes, while ESCRT-III also regulates Vps4. The studies presented in this proposal apply biochemical approaches to probe the enzymatic activity of Vps4, the regulation of Vps4 by ESCRT-III, and the mechanism by which Vps4-stimulated ESCRT-III dissociation facilitates intralumenal vesicle formation. These inquiries are complemented by in vivo functional analyses in the model organism Saccharomyces cerevisiae. Completion of this experimental plan will provide insight into the conserved evolutionary function of ESCRT-III and Vps4 in membrane constriction during MVB sorting, viral budding and cytokinesis.

描述（由申请人提供）：多囊体（MVB）排序是内吞途径内的关键过程，其中内体膜芽中的部分进入内体管腔。未能靶向活化的生长因子受体进入MVB途径会导致延长信号传导，这可能导致生物体发育中的肿瘤发生和缺陷。上皮钠通道的MVB靶向缺陷导致遗传的高血压形式（Liddle综合征）。神经退行性疾病与MVB途径的功能障碍有关，通过该途径的脂质异常运输也有助于许多人类疾病状态，包括动脉粥样硬化。 MVB排序是由运输（ESCRT-0，I，II和III）所需的内体分类复合物以及包括AAA-ATPase VPS4在内的相关因素介导的。除了在MVB排序中的作用外，ESCRT和VPS4还被包膜病毒（例如HIV-1和埃博拉病毒）篡夺以执行其细胞出口。此外，ESCRT和VPS4在细胞因子过程中有助于膜脱落。这些示例突出了许多受ESCRT功能以及功能障碍发生的疾病影响的过程。 VPS4和ESCRT-III在MVB分类，病毒萌芽和膜脱落中发生的相似拓扑（远离细胞质）的膜变形过程中以协调的方式起作用。这些过程需要通过VPS4 ATP水解将ESCRT-III解离，而ESCRT-III也调节VPS4。该提案中介绍的研究采用生化方法来探测VPS4的酶促活性，ESCRT-III对VPS4的调节以及VPS4刺激ESCRT-III解离的机制促进了内部囊泡的内部形成。这些查询在模型生物体酿酒酵母中的体内功能分析得到了补充。该实验计划的完成将洞悉MVB分类，病毒萌芽和细胞动力学期间ESCRT-III和VPS4在膜收缩中的保守进化功能。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of Vps4 during MVB sorting and cytokinesis.

DOI：
10.1111/j.1600-0854.2011.01230.x
发表时间：
2011-10
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
0
作者：
Babst M;Davies BA;Katzmann DJ
通讯作者：
Katzmann DJ

ESCRT-independent budding of HIV-1 gag virus-like particles from Saccharomyces cerevisiae spheroplasts.

来自酿酒酵母原生质球的 HIV-1 gag 病毒样颗粒的 ESCRT 独立出芽。

DOI：
10.1371/journal.pone.0052603
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Norgan,AndrewP;Lee,JacquelineRE;Oestreich,AndreaJ;Payne,JohannaA;Krueger,EugeneW;Katzmann,DavidJ
通讯作者：
Katzmann,DavidJ

Conformational Changes in the Endosomal Sorting Complex Required for the Transport III Subunit Ist1 Lead to Distinct Modes of ATPase Vps4 Regulation.

运输 III 亚基 Ist1 所需的内体分选复合物的构象变化导致 ATPase Vps4 调节的不同模式。