Toxoplasma gondii association with host mitochondria requires key mitochondrial protein import machinery.
Toxoplasma gondii association with host mitochondria requires key mitochondrial protein import machinery.
复制标题
弓形虫与宿主线粒体的结合需要关键的线粒体蛋白输入机制。
DOI：
10.1073/pnas.2013336118
复制
发表时间：
2021-03-23
影响因子：
11.1
通讯作者：
Boyle JP
中科院分区：
文献类型：
--
作者：
Blank ML;Xia J;Morcos MM;Sun M;Cantrell PS;Liu Y;Zeng X;Powell CJ;Yates N;Boulanger MJ;Boyle JP
许多病原体操纵宿主环境以促进其存活并最终传播。刚地弓形虫是一种细胞内寄生虫，可导致免疫系统减弱的人患病，也不例外。T.弓形虫对宿主细胞的感染是宿主线粒体在含有寄生虫的空泡周围的重新定位。在这里，我们已经确定了两个宿主蛋白质所需的T。弓形虫操纵宿主线粒体，两者都参与线粒体蛋白质输入。这一发现是寄生虫基因进化到特异性靶向细胞器表面宿主受体的一个显著例子。宿主线粒体缔合（HMA）是弓形虫感染宿主细胞过程中的一种常见现象。霸王弓形虫基因座线粒体相关因子1（MAF 1）是HMA所必需的，并且MAF 1编码分泌的致密颗粒效应蛋白的不同旁系同源物，其中一些介导HMA表型（MAF 1b旁系同源物驱动HMA; MAF 1a旁系同源物不驱动HMA）。为了鉴定MAF 1b介导的HMA所需的宿主蛋白，我们对感染了表达MAF 1b、MAF 1a和HMA不胜任的MAF 1b突变体的II型寄生虫的宿主细胞进行了无偏倚、无标记的定量蛋白质组学研究。在这些样本中，我们鉴定了101，360种MAF 1相互作用蛋白，但只有13种在MAF 1b下拉中显著且独特地富集。基因产物包括多种与线粒体相关的蛋白质，包括那些运输到线粒体外膜的蛋白质。基于后续的内切核糖核酸酶制备的短干扰RNA（esiRNA）实验靶向这些候选MAF 1b靶向宿主因子，我们确定线粒体受体蛋白TOM 70和HMA特异性伴侣蛋白HSPA 9是HMA的重要介质。此外，富集的寄生虫空泡膜界面处的TOM 70表明寄生虫驱动隔离的寄生虫。这些结果表明，T。弓形虫空泡和宿主线粒体之间的相互作用的特征在于单个寄生虫效应子和多个靶宿主蛋白之间的相互作用，其中一些对于HMA表型本身是关键的。这个复杂的功能成员的阐明将使我们能够解释HMA和宿主细胞的生物学变化之间的联系。
Many pathogens manipulate the host environment to promote their survival and eventual transmission. Toxoplasma gondii, an intracellular parasite that can cause disease in those with weakened immune systems, is no exception. One of the more dramatic effects of T. gondii infection on the host cell is a relocalization of the host mitochondria around the parasite-containing vacuole. Here, we have identified two host proteins that are required for T. gondii manipulation of host mitochondria, both of which are involved in mitochondrial protein import. This discovery is a remarkable example of a parasite gene evolving to specifically target a host receptor on the surface of an organelle. Host mitochondrial association (HMA) is a well-known phenomenon during Toxoplasma gondii infection of the host cell. The T. gondii locus mitochondrial association factor 1 (MAF1) is required for HMA and MAF1 encodes distinct paralogs of secreted dense granule effector proteins, some of which mediate the HMA phenotype (MAF1b paralogs drive HMA; MAF1a paralogs do not). To identify host proteins required for MAF1b-mediated HMA, we performed unbiased, label-free quantitative proteomics on host cells infected with type II parasites expressing MAF1b, MAF1a, and an HMA-incompetent MAF1b mutant. Across these samples, we identified ∼1,360 MAF1-interacting proteins, but only 13 that were significantly and uniquely enriched in MAF1b pull-downs. The gene products include multiple mitochondria-associated proteins, including those that traffic to the mitochondrial outer membrane. Based on follow-up endoribonuclease-prepared short interfering RNA (esiRNA) experiments targeting these candidate MAF1b-targeted host factors, we determined that the mitochondrial receptor protein TOM70 and mitochondria-specific chaperone HSPA9 were essential mediators of HMA. Additionally, the enrichment of TOM70 at the parasitophorous vacuole membrane interface suggests parasite-driven sequestration of TOM70 by the parasite. These results show that the interface between the T. gondii vacuole and the host mitochondria is characterized by interactions between a single parasite effector and multiple target host proteins, some of which are critical for the HMA phenotype itself. The elucidation of the functional members of this complex will permit us to explain the link between HMA and changes in the biology of the host cell.
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DOI：
10.1083/jcb.201708044
发表时间：
2018-04-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Backes S;Hess S;Boos F;Woellhaf MW;Gödel S;Jung M;Mühlhaus T;Herrmann JM
通讯作者：
Herrmann JM
影响因子：
4
作者：
Dubey, JP;Sreekumar, C
通讯作者：
Sreekumar, C
DOI：
10.1016/j.bbamcr.2016.01.019
发表时间：
2016-10-01
影响因子：
5.1
作者：
Colombini, Marco
通讯作者：
Colombini, Marco
影响因子：
4.8
作者：
Kelly, Felice D.;Wei, Brian M.;Boothroyd, John C.
通讯作者：
Boothroyd, John C.
影响因子：
3.6
作者：
Blank, Matthew L.;Parker, Michelle L.;Boyle, Jon P.
通讯作者：
Boyle, Jon P.