ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18.
ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18.
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DOI：
10.1084/jem.20101660
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发表时间：
2011-07-04
期刊：
影响因子：
--
通讯作者：
Takeda K
中科院分区：
文献类型：
--
作者：
Yamamoto M;Ma JS;Mueller C;Kamiyama N;Saiga H;Kubo E;Kimura T;Okamoto T;Okuyama M;Kayama H;Nagamune K;Takashima S;Matsuura Y;Soldati-Favre D;Takeda K
弓形虫毒力因子 ROP18 靶向宿主细胞中内质网结合的转录因子 ATF6β，通过蛋白酶体依赖性降解导致 ATF6β 的有害损失。 ROP18 激酶已被确定为关键的毒力决定因素，赋予 I 型弓形虫菌株高死亡率表型特征。这种主要效应分子在入侵过程中由菱形体分泌到宿主细胞中。然而，人们对这种激酶发挥致病作用的分子机制仍知之甚少。在这项研究中，我们发现 ROP18 靶向宿主内质网结合的转录因子 ATF6β。 ROP18 基因的破坏会严重损害 I 型 RH 菌株引起的急性弓形虫病。由于另一种毒力因子 ROP16 激酶通过其 N 端部分调节免疫反应，因此我们重点关注 ROP18 N 端在颠覆宿主细胞功能中的作用。 ROP18 的 N 端延伸通过与 ATF6β 相互作用并使其不稳定，从而导致 ATF6β 依赖性致病性。 ROP18 的激酶活性对于 ATF6β 的蛋白酶体依赖性降解和寄生虫毒力至关重要。与 ATF6β 在抵抗这种细胞内病原体中的关键作用一致，ATF6β 缺陷的小鼠表现出对 ROP18 缺陷寄生虫感染的高度易感性。结果表明，干扰 ATF6β 依赖性免疫反应是 ROP18 诱导的一种新的致病机制。
Toxoplasma virulence factor ROP18 targets endoplasmic reticulum–bound transcription factor ATF6β in the host cell, leading to the detrimental loss of ATF6β through proteasome-dependent degradation. The ROP18 kinase has been identified as a key virulence determinant conferring a high mortality phenotype characteristic of type I Toxoplasma gondii strains. This major effector molecule is secreted by the rhoptries into the host cells during invasion; however, the molecular mechanisms by which this kinase exerts its pathogenic action remain poorly understood. In this study, we show that ROP18 targets the host endoplasmic reticulum–bound transcription factor ATF6β. Disruption of the ROP18 gene severely impairs acute toxoplasmosis by the type I RH strain. Because another virulence factor ROP16 kinase modulates immune responses through its N-terminal portion, we focus on the role of the N terminus of ROP18 in the subversion of host cellular functions. The N-terminal extension of ROP18 contributes to ATF6β-dependent pathogenicity by interacting with ATF6β and destabilizing it. The kinase activity of ROP18 is essential for proteasome-dependent degradation of ATF6β and for parasite virulence. Consistent with a key role for ATF6β in resistance against this intracellular pathogen, ATF6β-deficient mice exhibit a high susceptibility to infection by ROP18-deficient parasites. The results reveal that interference with ATF6β-dependent immune responses is a novel pathogenic mechanism induced by ROP18.
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影响因子：
3.4
作者：
Khaminets A;Hunn JP;Könen-Waisman S;Zhao YO;Preukschat D;Coers J;Boyle JP;Ong YC;Boothroyd JC;Reichmann G;Howard JC
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作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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