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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金, 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 巨细胞病毒广泛传播于所有地理位置和社会经济群体,到40岁时感染美国85%的成年人。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。这项研究是一年半前与普林斯顿大学汤姆·申克的实验室合作发起的。从那时起,我们已经分离了各种蛋白A或GFP标记的HCMV病毒蛋白,以识别它们在感染的不同阶段的宿主和病毒相互作用伙伴。在过去的一年里,我们研究了几种病毒蛋白的相互作用伙伴,包括UL83、UL121、UL38、UL99和US22。这些研究中的每一项都强调了HCMV利用新的方式来操纵和接管细胞。 人类巨细胞病毒蛋白改变宿主细胞以利于病毒复制。这些病毒蛋白包括防止细胞凋亡的pUL38。为了研究pUL38的作用方式,我们对病毒基因组进行了修饰,编码了一个表位标记的pUL38,并用快速免疫亲和纯化的方法分离出与pUL38相互作用的宿主蛋白,然后用质谱仪对其进行鉴定。已鉴定的细胞蛋白之一是结节性硬化症肿瘤抑制蛋白复合体(TSC1/2)的组成部分TSC2。TSC1/2整合应激信号并调节哺乳动物雷帕霉素复合体1(MTORC1)的靶标,mTORC1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体。我们发现在野生型巨细胞病毒感染的细胞中,pUL38与TSC1和TSC2相互作用。此外,TSC1/2不能调节表达pUL38的细胞中的mTORC1,这些细胞表现出巨细胞病毒感染的增大特征。因此,pUL38至少部分地通过阻断细胞对压力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UL38通过拮抗结节硬化症蛋白复合体来抑制宿主细胞应激反应。首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容2008年3(4):253-62 最近,我们准备了另外两份手稿,其中使用免疫隔离质谱仪来获得关于病毒蛋白在宿主中功能的线索(见下文)。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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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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