FOLLOWING THE FATE OF HCMV GENE PRODUCTS IN HOST CELLS

追踪 HCMV 基因产物在宿主细胞中的命运

基本信息

  • 批准号:
    8169121
  • 负责人:
  • 金额:
    $ 4.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-03-01 至 2011-02-28
  • 项目状态:
    已结题

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cytomegalovirus is widely spread throughout all geographic locations and socioeconomic group and infects 85% of adults in United States by 40 years of age. Our aim is to study the interactions of human cytomegalovirus with cellular proteins, and gain insights into cellular pathways modulated by herpesviruses. This study was initiated one and a half years ago in collaboration with the laboratory of Tom Shenk at Princeton University. Since then, we have isolated a variety of Protein A- or GFP-tagged HCMV viral proteins identifying their host and viral interacting partners at various stages of infections. During this last year, we have studied the interacting partners of several viral proteins, including UL83, UL121, UL38, UL99, and US22. Each of these studies highlighted new ways that HCMV utilizes to manipulate and take over the cell. Human cytomegalovirus proteins alter host cells to favor virus replication. These viral proteins include pUL38, which prevents apoptosis. To characterize the mode of action of pUL38, we modified the viral genome to encode an epitope-tagged pUL38 and used rapid immunoaffinity purification to isolate pUL38-interacting host proteins, which were then identified by mass spectrometry. One of the cellular proteins identified was TSC2, a constituent of the tuberous sclerosis tumor suppressor protein complex (TSC1/2). TSC1/2 integrates stress signals and regulates the mammalian target of rapamycin complex 1 (mTORC1), a protein complex that responds to stress by limiting protein synthesis and cell growth. We showed that pUL38 interacts with TSC1 and TSC2 in cells infected with wild-type cytomegalovirus. Furthermore, TSC1/2 failed to regulate mTORC1 in cells expressing pUL38, and these cells exhibited the enlarged size characteristic of cytomegalovirus infection. Thus, pUL38 supports virus replication at least in part by blocking cellular responses to stress. A manuscript describing this work has been published: Human cytomegalovirus protein UL38 inhibits host cell stress responses by antagonizing the tuberous sclerosis protein complex. Moorman NJ, Cristea IM, Terhune SS, Rout MP, Chait BT, Shenk T. Cell Host Microbe. 2008 3(4):253-62. Most recently, we have prepared two additional manuscrpts in which immunoisolation mass spectrometry was used to gain clues as to the function of viral proteins in their hosts (see below)
这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者(PI)可能从另一个NIH来源获得了主要资金, 因此可以在其他CRISP条目中表示。所列机构为 研究中心,而研究中心不一定是研究者所在的机构。 巨细胞病毒在所有地理位置和社会经济群体中广泛传播,并在美国40岁以下的成年人中感染85%。我们的目的是研究人类巨细胞病毒与细胞蛋白的相互作用,并深入了解疱疹病毒调控的细胞途径。这项研究是在一年半前与普林斯顿大学的Tom Shenk实验室合作发起的。从那时起,我们已经分离出各种蛋白A或GFP标记的HCMV病毒蛋白,在感染的各个阶段鉴定其宿主和病毒相互作用的伴侣。在过去的一年中,我们研究了几种病毒蛋白的相互作用伴侣,包括UL 83,UL 121,UL 38,UL 99和US 22。这些研究中的每一项都强调了HCMV用来操纵和接管细胞的新方法。 人巨细胞病毒蛋白改变宿主细胞以利于病毒复制。这些病毒蛋白包括pUL 38,其防止细胞凋亡。为了表征pUL 38的作用模式,我们修改了病毒基因组以编码表位标记的pUL 38,并使用快速免疫亲和纯化来分离pUL 38相互作用的宿主蛋白,然后通过质谱鉴定。鉴定的细胞蛋白之一是TSC 2,它是结节性硬化症肿瘤抑制蛋白复合物(TSC 1/2)的组成部分。TSC 1/2整合应激信号并调节雷帕霉素复合物1(mTORC 1)的哺乳动物靶标,mTORC 1是一种通过限制蛋白质合成和细胞生长来响应应激的蛋白质复合物。我们发现,pUL 38与TSC 1和TSC 2在感染野生型巨细胞病毒的细胞中相互作用。此外,TSC 1/2不能调节表达pUL 38的细胞中的mTORC 1,并且这些细胞表现出巨细胞病毒感染的特征性的增大的尺寸。因此,pUL 38至少部分通过阻断细胞对应激的反应来支持病毒复制。描述这项工作的手稿已经出版: 人巨细胞病毒蛋白UL 38通过拮抗结节性硬化症蛋白复合物抑制宿主细胞应激反应。Moorman NJ,Cristea IM,Terhune SS,Rout MP,Chait BT,Shenk T.细胞宿主微生物。2008 3(4):253-62. 最近,我们准备了另外两份手册,其中使用免疫隔离质谱法来获得关于病毒蛋白在其宿主中的功能的线索(见下文)。

项目成果

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THOMAS E SHENK其他文献

THOMAS E SHENK的其他文献

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{{ truncateString('THOMAS E SHENK', 18)}}的其他基金

Human cytomegalovirus-induced alterations to cell-surface adhesion proteins
人巨细胞病毒诱导的细胞表面粘附蛋白改变
  • 批准号:
    8990958
  • 财政年份:
    2015
  • 资助金额:
    $ 4.65万
  • 项目类别:
Human cytomegalovirus-induced alterations to cell-surface adhesion proteins
人巨细胞病毒诱导的细胞表面粘附蛋白改变
  • 批准号:
    9195706
  • 财政年份:
    2015
  • 资助金额:
    $ 4.65万
  • 项目类别:
Human cytomegalovirus-induced alterations to cell-surface adhesion proteins
人巨细胞病毒诱导的细胞表面粘附蛋白改变
  • 批准号:
    8885082
  • 财政年份:
    2015
  • 资助金额:
    $ 4.65万
  • 项目类别:
FOLLOWING THE FATE OF HCMV GENE PRODUCTS IN HOST CELLS
追踪 HCMV 基因产物在宿主细胞中的命运
  • 批准号:
    8361504
  • 财政年份:
    2011
  • 资助金额:
    $ 4.65万
  • 项目类别:
Human cytomegalovirus latency in cultured monocytes
培养单核细胞中的人巨细胞病毒潜伏期
  • 批准号:
    8416378
  • 财政年份:
    2010
  • 资助金额:
    $ 4.65万
  • 项目类别:
Human cytomegalovirus latency in cultured monocytes
培养单核细胞中的人巨细胞病毒潜伏期
  • 批准号:
    7859083
  • 财政年份:
    2010
  • 资助金额:
    $ 4.65万
  • 项目类别:
Human cytomegalovirus latency in cultured monocytes
培养单核细胞中的人巨细胞病毒潜伏期
  • 批准号:
    8019543
  • 财政年份:
    2010
  • 资助金额:
    $ 4.65万
  • 项目类别:
Human cytomegalovirus latency in cultured monocytes
培养单核细胞中的人巨细胞病毒潜伏期
  • 批准号:
    8605153
  • 财政年份:
    2010
  • 资助金额:
    $ 4.65万
  • 项目类别:
Human cytomegalovirus latency in cultured monocytes
培养单核细胞中的人巨细胞病毒潜伏期
  • 批准号:
    8212375
  • 财政年份:
    2010
  • 资助金额:
    $ 4.65万
  • 项目类别:
PROJECT 3
项目3
  • 批准号:
    7905601
  • 财政年份:
    2009
  • 资助金额:
    $ 4.65万
  • 项目类别:

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