Intracellular trafficking of the mitochondrial targeting toxin VacA from Helicobacter pylori

幽门螺杆菌线粒体靶向毒素 VacA 的细胞内运输

基本信息

项目摘要

 DESCRIPTION (provided by applicant): This exploratory R21 application proposes studies to identify and characterize the mechanism by which the vacuolating cytotoxin (VacA), an important virulence factor produced by the human gastric pathogen Helicobacter pylori, targets mitochondria within intoxicated host cells. VacA is a membrane-channel forming toxin, which subsequent to binding the surface of host cells, is taken up from the plasma membrane into VacA- containing vesicles (VCVs), and subsequently targets the inner membrane of mitochondria, resulting in metabolic dysfunction and cell death. Here, we propose studies that challenge canonical models of host cell intoxication by intracellular-acting bacterial toxins, whic generally require the translocation of enzymatic active fragments from the endolysosomal system or endoplasmic reticulum to the cytosol prior to toxin- mediated modification of intracellular targets. Rather, subsequent to internalization, we propose that VacA is transported within VCVs to mitochondria, where the toxin is then directly transferred to mitochondria. However, the identity of VCV proteins important for VacA targeting/trafficking to mitochondria is difficult to predict, due in part to the fact that until very recently, mitochondria were not generlly thought to receive protein cargo from the endolysosomal system and, as a consequence, almost nothing is known about intracellular trafficking compartments destined for mitochondria. To address this gap in knowledge, we will evaluate the hypothesis that VacA-targeting of mitochondria requires remodeling of VacA-containing vesicles (VCVs) from early endosomal-like compartments to vesicles that are functionally competent for targeting and fusion with mitochondria. Using magnetic-based separation methods to isolate iron-enriched VCVs from cells at different stages of intoxication for proteome analysis, we will identify changes in VCV-associated proteins, and, characterize their functional importance for VacA targeting of mitochondria and mitochondrial dysfunction. These studies will provide the first detailed characterization of the host cell machinery that is important for mitochondrial targeting, and, contribute to our understanding of the fundamental biology underlying the modulation of host cells by VacA.


项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Steven R. Blanke其他文献

Helicobacter pylori VacA, a paradigm for toxin multifunctionality
幽门螺杆菌 VacA,毒素多功能性的范例
  • DOI:
    10.1038/nrmicro1095
  • 发表时间:
    2005-03-10
  • 期刊:
  • 影响因子:
    103.300
  • 作者:
    Timothy L. Cover;Steven R. Blanke
  • 通讯作者:
    Steven R. Blanke
Host cell sensing and restoration of mitochondrial function and metabolism within emHelicobacter pylori/em VacA intoxicated cells
宿主细胞对幽门螺杆菌 VacA 中毒细胞内线粒体功能和代谢的感知与恢复
  • DOI:
    10.1128/mbio.02117-23
  • 发表时间:
    2023-09-22
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Ami Y. Seeger;Faisal Zaidi;Sammy Alhayek;Rachel M. Jones;Huzaifa Zohair;Robin L. Holland;Ik-Jung Kim;Steven R. Blanke
  • 通讯作者:
    Steven R. Blanke
A bacterial genotoxin reveals a p53-proteasome-LC3 regulatory axis that drives the suppression of autophagy in cells experiencing sublethal DNA damage
一种细菌基因毒素揭示了一个 p53-蛋白酶体-LC3 调节轴,该轴驱动经历亚致死性 DNA 损伤的细胞中自噬的抑制。
  • DOI:
    10.1016/j.isci.2025.112118
  • 发表时间:
    2025-04-18
  • 期刊:
  • 影响因子:
    4.100
  • 作者:
    D’Feau J. Lieu;Molly K. Crowder;Jordan R. Kryza;Batcha Tamilselvam;Paul J. Kaminski;Ik-Jung Kim;Ying-Xing Li;Eunji Jeong;Michidmaa Enkhbaatar;Henry Chen;Sophia B. Son;Hanlin Mok;Kenneth A. Bradley;Heidi Phillips;Steven R. Blanke
  • 通讯作者:
    Steven R. Blanke

Steven R. Blanke的其他文献

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{{ truncateString('Steven R. Blanke', 18)}}的其他基金

Cytolethal Distending Toxin and Intestinal Homeostasis
细胞致死膨胀毒素和肠道稳态
  • 批准号:
    10371246
  • 财政年份:
    2021
  • 资助金额:
    $ 18.93万
  • 项目类别:
Intracellular trafficking of the mitochondrial targeting toxin VacA from Helicobacter pylori
幽门螺杆菌线粒体靶向毒素 VacA 的细胞内运输
  • 批准号:
    9054794
  • 财政年份:
    2015
  • 资助金额:
    $ 18.93万
  • 项目类别:
Bacillus-containing vacuole-mediated interactions of Bacillus anthracis with macrophages
含芽孢杆菌液泡介导的炭疽芽孢杆菌与巨噬细胞的相互作用
  • 批准号:
    8829616
  • 财政年份:
    2015
  • 资助金额:
    $ 18.93万
  • 项目类别:
Molecular Mechanisms of the H. pylori Vacuolating Toxin
幽门螺杆菌空泡毒素的分子机制
  • 批准号:
    8136829
  • 财政年份:
    2010
  • 资助金额:
    $ 18.93万
  • 项目类别:
C. jejuni Cytolethal Distending Toxin Cell Interactions
空肠弯曲菌细胞致死膨胀毒素细胞相互作用
  • 批准号:
    6757748
  • 财政年份:
    2004
  • 资助金额:
    $ 18.93万
  • 项目类别:
C. jejuni Cytolethal Distending Toxin Cell Interactions
空肠弯曲菌细胞致死膨胀毒素细胞相互作用
  • 批准号:
    7133491
  • 财政年份:
    2004
  • 资助金额:
    $ 18.93万
  • 项目类别:
C. jejuni Cytolethal Distending Toxin Cell Interactions
空肠弯曲菌细胞致死膨胀毒素细胞相互作用
  • 批准号:
    6879065
  • 财政年份:
    2004
  • 资助金额:
    $ 18.93万
  • 项目类别:
Blocking Cellular Intoxication by Bacterial Toxins
阻止细菌毒素引起的细胞中毒
  • 批准号:
    6561325
  • 财政年份:
    2002
  • 资助金额:
    $ 18.93万
  • 项目类别:
Blocking Cellular Intoxication by Bacterial Toxins
阻止细菌毒素引起的细胞中毒
  • 批准号:
    6653079
  • 财政年份:
    2002
  • 资助金额:
    $ 18.93万
  • 项目类别:
Molecular Mechanisms of the H. pylori Vacuolating Toxin
幽门螺杆菌空泡毒素的分子机制
  • 批准号:
    8337881
  • 财政年份:
    2000
  • 资助金额:
    $ 18.93万
  • 项目类别:

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