Dynamic virus-driven remodeling of ER-mitochondria contacts

内质网-线粒体接触的动态病毒驱动重塑

基本信息

  • 批准号:
    10608035
  • 负责人:
  • 金额:
    $ 41.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-19 至 2027-07-31
  • 项目状态:
    未结题

项目摘要

Viruses have evolved elegant strategies to manipulate host cell machinery and rewire core cellular pathways to facilitate productive infection, including enhancing metabolic output and maintaining cell viability. To accomplish this, viruses exert an extensive network of dynamic molecular interactions with cellular organelles. As the functions of organelles are intimately associated with the regulation of their composition, shape, and localization, the control of organelle structure-function relationships is at the core of clarifying the outcome of an infection. While many examples of virus-induced organelle remodeling have been described, very little is understood about how organelle structures engender specific functions. Our lab has characterized a previously unrecognized aspect of viral infection, which is that human viruses globally control organelle remodeling by dramatically rewiring inter- and intra-organelle membrane contact sites (MCS). Using a hybrid quantitative proteomics and super resolution microscopy approach, we demonstrated exquisite reorganization in MCS networks engaged by a broad range of human viruses, including both ancient (herpesviruses) and rapidly adapting (influenza and beta- coronavirus) viruses. We further discovered that infection with the ubiquitous herpesvirus human cytomegalovirus (HCMV) triggers a new specialized MCS structure, mitochondria-ER encapsulations that we termed MENC. We determined that HCMV infection drives predominantly fission at the mitochondrial periphery, and that the fragmented mitochondria enter MENCs and retain their bioenergetic activity. How the infection induces MENC formation and the function of this newly reported structure remain unknown. We propose that MENCs provide a unifying explanation for the longstanding paradox of how certain viruses such as HCMV increase mitochondrial bioenergetic output, despite inducing mitochondrial fragmentation. Our central hypothesis is that HCMV remodels inter- and intra-organelle connections, generating MENCs, which act to protect and stabilize the bioenergetic capacity of fragmented mitochondria. Using a multidisciplinary approach that combines molecular virology with cutting-edge approaches in quantitative proteomics, live super resolution microscopy, ultrastructural electron microscopy, metabolomics, and lipidomics, in Aim 1, we will define the mechanisms underlying the formation and function of MENCs during HCMV infection. In Aim 2, we will establish what signaling cues from HCMV-induced three-way contacts among the ER, mitochondria, and lysosome stimulate peripheral mitochondria fission and elevate bioenergetic respiration. In Aim 3, we will characterize the viral factors that coordinate ER-mitochondria MCS rewiring. Collectively, our study will link newly discovered aspects of virus-orchestrated MCS networking to new two-way and three-way organelle structure-function relationships that underlie fundamental cellular mechanisms, including mitochondrial bioenergetics and autophagic turnover. In doing so, our study will open research areas in how viruses exploit the functional capacities of remodeled organelles for infection, which have broad implications for viral pathogenesis and metabolic disorders.
病毒已经进化出优雅的策略来操纵宿主细胞机制并重新连接核心细胞通路, 促进生产性感染,包括增强代谢输出和维持细胞活力。完成 因此,病毒与细胞器发挥广泛的动态分子相互作用网络。为 细胞器的功能与其组成、形状和定位的调节密切相关, 细胞器结构-功能关系的控制是阐明感染结果的核心。 虽然已经描述了许多病毒诱导的细胞器重塑的例子,但对病毒诱导的细胞器重塑的理解很少。 细胞器结构如何产生特定功能。我们的实验室发现了一种 病毒感染的一个方面,即人类病毒通过显着地控制细胞器重塑, 重新连接细胞器内和细胞器间膜接触部位(MCS)。使用混合定量蛋白质组学和 超分辨率显微镜的方法,我们证明了精致的重组MCS网络从事 广泛的人类病毒,包括古老的(疱疹病毒)和快速适应的(流感和β- 冠状病毒)病毒。我们进一步发现,感染普遍存在的人类疱疹病毒, 巨细胞病毒(HCMV)触发了一种新的专门的MCS结构,即巨噬细胞-ER介导, 称为MENC。我们确定HCMV感染主要驱动线粒体周边的分裂, 并且破碎的线粒体进入MENC并保持其生物能量活性。感染是如何 诱导MENC的形成,这种新报道的结构的功能仍然未知。我们建议 MENC为某些病毒(如HCMV) 增加线粒体生物能量输出,尽管诱导线粒体碎裂。我们的核心假设 HCMV重塑细胞器间和细胞器内的连接,产生MENC,其作用是保护和 稳定破碎线粒体的生物能量能力。采用多学科方法, 分子病毒学与定量蛋白质组学,活超分辨率显微镜, 超微结构电子显微镜,代谢组学和脂质组学,在目标1中,我们将定义机制 在HCMV感染过程中MENC的形成和功能的基础。在目标2中,我们将确定 来自HCMV诱导的ER、线粒体和溶酶体之间的三向接触的信号线索刺激 外周线粒体分裂并提高生物能呼吸。在目标3中,我们将描述病毒 协调ER-线粒体MCS重新布线的因子。总的来说,我们的研究将把新发现的方面 病毒协调的MCS网络的新的双向和三向细胞器结构-功能关系 这是基本细胞机制的基础,包括线粒体生物能量学和自噬周转。 在这样做的过程中,我们的研究将打开病毒如何利用重塑的功能能力的研究领域。 细胞器的感染,这对病毒的发病机制和代谢紊乱有广泛的影响。

项目成果

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Ileana M. Cristea其他文献

The protein composition of human adenovirus replication compartments
人腺病毒复制区室的蛋白质组成
  • DOI:
    10.1128/mbio.02144-24
  • 发表时间:
    2024-11-29
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Paloma Hidalgo;Amada Torres;Pierre M. Jean Beltran;Gamaliel López-Leal;Luca D. Bertzbach;Thomas Dobner;S. J. Flint;Ileana M. Cristea;Ramón A. González
  • 通讯作者:
    Ramón A. González
emIn vitro/em and emex vivo/em proteomics of emMycobacterium marinum/em biofilms and the development of biofilm-binding synthetic nanobodies
海分枝杆菌生物膜的体外和体内蛋白质组学以及生物膜结合合成纳米抗体的开发
  • DOI:
    10.1128/msystems.01073-22
  • 发表时间:
    2023-05-03
  • 期刊:
  • 影响因子:
    4.600
  • 作者:
    Milka Marjut Hammarén;Hanna Luukinen;Alina Sillanpää;Kim Remans;Karine Lapouge;Tânia Custódio;Christian Löw;Henna Myllymäki;Toni Montonen;Markus Seeger;Joseph Robertson;Tuula A. Nyman;Kirsi Savijoki;Mataleena Parikka;Ileana M. Cristea;Paul Cos
  • 通讯作者:
    Paul Cos
Fpa (YlaN) is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression in emStaphylococcus aureus/em
Fpa(YlaN)是一种铁(II)结合蛋白,其作用是缓解金黄色葡萄球菌中 Fur 介导的基因表达抑制。
  • DOI:
    10.1128/mbio.02310-24
  • 发表时间:
    2024-10-09
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Jeffrey M. Boyd;Kylie Ryan Kaler;Karla Esquilín-Lebrón;Ashley Pall;Courtney J. Campbell;Mary E. Foley;Gustavo Rios-Delgado;Emilee M. Mustor;Timothy G. Stephens;Hannah Bovermann;Todd M. Greco;Ileana M. Cristea;Valerie J. Carabetta;William N. Beavers;Debashish Bhattacharya;Eric P. Skaar;Lindsey N. Shaw;Timothy L. Stemmler
  • 通讯作者:
    Timothy L. Stemmler
A Primer on Proteomic Characterization of Intercellular Communication in a Virus Microenvironment
病毒微环境中细胞间通讯的蛋白质组学表征入门
  • DOI:
    10.1016/j.mcpro.2025.100913
  • 发表时间:
    2025-03-01
  • 期刊:
  • 影响因子:
    5.500
  • 作者:
    James C. Kostas;Colter S. Brainard;Ileana M. Cristea
  • 通讯作者:
    Ileana M. Cristea
Liquid–liquid phase separation in innate immunity
天然免疫中的液-液相分离
  • DOI:
    10.1016/j.it.2024.04.009
  • 发表时间:
    2024-06-01
  • 期刊:
  • 影响因子:
    13.900
  • 作者:
    Dawei Liu;Jinhang Yang;Ileana M. Cristea
  • 通讯作者:
    Ileana M. Cristea

Ileana M. Cristea的其他文献

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{{ truncateString('Ileana M. Cristea', 18)}}的其他基金

Methods and Logic in Molecular Biology Training Program
分子生物学方法与逻辑培训计划
  • 批准号:
    10721701
  • 财政年份:
    2023
  • 资助金额:
    $ 41.94万
  • 项目类别:
Dynamic virus-driven remodeling of ER-mitochondria contacts
内质网-线粒体接触的动态病毒驱动重塑
  • 批准号:
    10707412
  • 财政年份:
    2022
  • 资助金额:
    $ 41.94万
  • 项目类别:
Mechanisms mediating immune response upon sensing of nuclear viral DNA
感测核病毒 DNA 介导免疫反应的机制
  • 批准号:
    10266082
  • 财政年份:
    2015
  • 资助金额:
    $ 41.94万
  • 项目类别:
Mechanisms mediating immune response upon sensing of nuclear viral DNA
感测核病毒 DNA 介导免疫反应的机制
  • 批准号:
    9027921
  • 财政年份:
    2015
  • 资助金额:
    $ 41.94万
  • 项目类别:
Mechanisms mediating immune response upon sensing of nuclear viral DNA
感测核病毒 DNA 介导免疫反应的机制
  • 批准号:
    9973554
  • 财政年份:
    2015
  • 资助金额:
    $ 41.94万
  • 项目类别:
Mechanisms mediating immune response upon sensing of nuclear viral DNA
感测核病毒 DNA 介导免疫反应的机制
  • 批准号:
    10672215
  • 财政年份:
    2015
  • 资助金额:
    $ 41.94万
  • 项目类别:
Mechanisms mediating immune response upon sensing of nuclear viral DNA
感测核病毒 DNA 介导免疫反应的机制
  • 批准号:
    10456254
  • 财政年份:
    2015
  • 资助金额:
    $ 41.94万
  • 项目类别:
Host Factors Required for Dengue and Yellow Fever Virus Amplification
登革热和黄热病病毒扩增所需的宿主因素
  • 批准号:
    8522155
  • 财政年份:
    2012
  • 资助金额:
    $ 41.94万
  • 项目类别:
Host Factors Required for Dengue and Yellow Fever Virus Amplification
登革热和黄热病病毒扩增所需的宿主因素
  • 批准号:
    8391158
  • 财政年份:
    2012
  • 资助金额:
    $ 41.94万
  • 项目类别:
Proteomic Tools to Uncover the Role of Chromatin Remodeling in HIV-1 Infection
揭示染色质重塑在 HIV-1 感染中作用的蛋白质组学工具
  • 批准号:
    8117154
  • 财政年份:
    2008
  • 资助金额:
    $ 41.94万
  • 项目类别:

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