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Ubiquitin and Cell Cycle Regulation of Golgi Membrane Dynamics

泛素和高尔基膜动力学的细胞周期调节

基本信息

批准号：
8450844
负责人：
Yanzhuang Wang
金额：
$ 29.17万
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：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450844
关键词：
ATP phosphohydrolase Adaptor Signaling Protein Alzheimer&apos s Disease Animals Antibodies Autoimmune Diseases Binding Biochemical Biogenesis Biological Assay Capsid Proteins Cell Cycle Cell Cycle Regulation Cell division Cell physiology Cells Coat Protein Complex I Complex Coupled Cytosol Data Deubiquitinating Enzyme Disease Enzyme Inhibition Enzymes Eukaryotic Cell Functional disorder Goals Golgi Apparatus Growth Factor Hormones Huntington Disease In Vitro Incubated Knowledge Malignant Neoplasms Mediating Membrane Membrane Fusion Membrane Proteins Mitosis Mitotic Molecular Neurotransmitters Organelles Pathogenesis Phosphotransferases Play Process Protein Secretion Proteins Regulation Role SNAP receptor Structure Techniques Tubular formation UBA Domain Ubiquitin Ubiquitin Like Proteins Ubiquitination Vesicle Viral Cancer Virus Diseases Work base cofactor daughter cell enzyme substrate human disease in vivo insight knock-down multicatalytic endopeptidase complex mutant novel strategies overexpression protein degradation protein transport reconstitution secretory protein small hairpin RNA ubiquitin ligase ubiquitin-protein ligase uncontrolled cell growth

项目摘要

The Golgi complex is a membrane-bound organelle that serves as a central conduit for the processing of secretory proteins in all eukaryotic cells. Alterations in the Golgi structure and function have been associated with a variety of human diseases, including autoimmune disease, Huntington's and Alzheimer's diseases, viral infections and cancer. A better understanding of the relationship between the normal Golgi structure formation and its vital cellular function is required before its role in human disease can be understood. Golgi biogenesis during cell division is mediated by a disassembly and reassembly process. It disassembles into tubularvesicular structures during mitosis, which are partitioned into the daughter cells where they are reassembled into a new Golgi apparatus. Reassembly is mediated by two ATPases (NSF and p97) that fuse the membranes.Our recent discovery that ubiquitin plays a role in p97-mediated Golgi membrane fusion opens a door for a new approach to uncover the underlying mechanism. Ubiquitination occurs during mitotic Golgi disassembly and is required for subsequent reassembly. Reassembly requires the interaction between the p97/p47 and monoubiquitin and the activity of the deubiquitinating enzyme, VCIP135, a cofactor of the p97/p47 complex. We hypothesize that ubiquitination operates as a general mechanism in regulation of Golgi membrane dynamics during the cell cycle. We will use a combination of biochemical and morphological approaches to elucidate how ubiquitination occurs during mitotic Golgi disassembly and how it regulates postmitotic reassembly. The specific aims are: 1) To identify the ubiquitin ligase (E3) and elucidate its function in vitro by inhibition of the enzyme and in vivo by knocking down the protein. 2) To identify the ubiquitinated substrate(s) on the Golgi and confirm it using the available ubiquitin ligase and deubiquitinase. 3) To elucidate the mechanism of ubiquitination in mitotic Golgi membrane dynamics. We will determine the interactions between the enzymes and the substrate(s) in relation to p97-mediated membrane fusion. We will control ubiquitination by manipulation of both the ubiquitin ligase and the deubiquitinating enzyme in cells using shRNA and overexpression techniques, and thus determine the effects on Golgi membrane reassembly at the end of mitosis. These studies will provide new insights into the molecular mechanisms of cell cycle regulation of Golgi membrane dynamics.

高尔基复合体是一种膜结合的细胞器，作为处理蛋白质的中心通道

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HACE1 (HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1).

HACE1（包含 E3 泛素蛋白连接酶 1 的 HECT 结构域和锚蛋白重复序列）。

DOI：
10.4267/2042/49701
发表时间：
2012
期刊：
Atlas of genetics and cytogenetics in oncology and haematology
影响因子：
0
作者：
Cui,Feng;Wang,Yanzhuang
通讯作者：
Wang,Yanzhuang

The ubiquitin ligase HACE1 regulates Golgi membrane dynamics during the cell cycle.

DOI：
10.1038/ncomms1509
发表时间：
2011-10-11
期刊：
Nature communications
影响因子：
16.6
作者：
通讯作者：

Direct selection of monoclonal phosphospecific antibodies without prior phosphoamino acid mapping.

直接选择单克隆磷酸化特异性抗体，无需事先进行磷酸氨基酸图谱分析。

DOI：
10.1074/jbc.m109.008730
发表时间：
2009
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Vielemeyer,Ole;Yuan,Hebao;Moutel,Sandrine;Saint-Fort,Rénette;Tang,Danming;Nizak,Clément;Goud,Bruno;Wang,Yanzhuang;Perez,Franck
通讯作者：
Perez,Franck

Monoubiquitination of Syntaxin 5 Regulates Golgi Membrane Dynamics during the Cell Cycle.

语法5的单泛素化调节细胞周期中的高尔基膜动力学。