EphrinA2 receptor (EphA2) is an invasion and intracellular signaling receptor for Chlamydia trachomatis.
EphrinA2 receptor (EphA2) is an invasion and intracellular signaling receptor for Chlamydia trachomatis.
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DOI：
10.1371/journal.ppat.1004846
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发表时间：
2015-04
期刊：
影响因子：
6.7
通讯作者：
Rudel T
中科院分区：
文献类型：
--
作者：
Subbarayal P;Karunakaran K;Winkler AC;Rother M;Gonzalez E;Meyer TF;Rudel T
专性细胞内细菌沙眼衣原体侵入宿主细胞，在被称为包涵体的膜结合的液泡内复制。多种不同的宿主蛋白被招募到包涵体中，并被功能调节以支持衣原体的发育。衣原体的入侵和复制诱导PI3信号通路的长期激活，这是有效复制所必需的。我们鉴定了细胞表面酪氨酸激酶EwitinA2受体(EphA2)是一种衣原体黏附和侵袭受体，它诱导PI3K激活，促进衣原体复制。干扰沙眼衣原体L2(CTR)与EphA2的结合，下调EphA2的表达或抑制EphA2的活性，可显著减少CTR的感染。CTR与细胞表面的EphA2相互作用并激活，导致CTR和受体内化。在衣原体复制过程中，EphA2保持活跃，在包涵体周围积累，并与PI3K的P85调节亚基相互作用，支持正常衣原体发育所需的PI3K/Akt信号通路的激活。过表达全长EphA2，而不是缺乏胞浆结构域的突变形式，增强了PI3K的激活和CTR的感染。尽管EphA2从细胞表面消失，但CTR感染通过激活ERK途径诱导EphA2上调，从而使感染细胞处于抗凋亡状态。EphA2作为进入和细胞内信号受体的意义也在泌尿生殖道沙眼衣原体D血清型中观察到。我们的发现为宿主细胞表面受体被用于入侵以及受体介导的细胞内信号转导促进衣原体复制提供了第一个证据。此外，细胞表面受体在包涵体膜上的结合是衣原体颠覆宿主细胞和诱导细胞凋亡抵抗的新机制。沙眼衣原体是导致眼部和性传播疾病的主要人类病原体，每年有数亿病例。衣原体在宿主细胞内以一种称为包涵体的膜结合的液泡进行复制。目前关于衣原体在复制过程中如何与宿主细胞沟通的概念是基于对与衣原体相互作用的宿主蛋白的鉴定。在这里，我们描述了沙眼衣原体-血清型L2和D使用EphA2作为与细菌一起内吞的黏附和进入受体，EphA2是人类受体酪氨酸激酶的最大类成员。衣原体通过细胞表面的EphA2受体在包涵体上发挥作用，以支持生长和复制，并使感染的细胞处于抗凋亡状态。因此，我们认为EphA2是一种尚未发现的重要表面和细胞内信号受体，对衣原体感染和发育至关重要。
The obligate intracellular bacterium Chlamydia trachomatis invades into host cells to replicate inside a membrane-bound vacuole called inclusion. Multiple different host proteins are recruited to the inclusion and are functionally modulated to support chlamydial development. Invaded and replicating Chlamydia induces a long-lasting activation of the PI3 kinase signaling pathway that is required for efficient replication. We identified the cell surface tyrosine kinase EphrinA2 receptor (EphA2) as a chlamydial adherence and invasion receptor that induces PI3 kinase (PI3K) activation, promoting chlamydial replication. Interfering with binding of C. trachomatis serovar L2 (Ctr) to EphA2, downregulation of EphA2 expression or inhibition of EphA2 activity significantly reduced Ctr infection. Ctr interacts with and activates EphA2 on the cell surface resulting in Ctr and receptor internalization. During chlamydial replication, EphA2 remains active accumulating around the inclusion and interacts with the p85 regulatory subunit of PI3K to support the activation of the PI3K/Akt signaling pathway that is required for normal chlamydial development. Overexpression of full length EphA2, but not the mutant form lacking the intracellular cytoplasmic domain, enhanced PI3K activation and Ctr infection. Despite the depletion of EphA2 from the cell surface, Ctr infection induces upregulation of EphA2 through the activation of the ERK pathway, which keeps the infected cell in an apoptosis-resistant state. The significance of EphA2 as an entry and intracellular signaling receptor was also observed with the urogenital C. trachomatis-serovar D. Our findings provide the first evidence for a host cell surface receptor that is exploited for invasion as well as for receptor-mediated intracellular signaling to facilitate chlamydial replication. In addition, the engagement of a cell surface receptor at the inclusion membrane is a new mechanism by which Chlamydia subverts the host cell and induces apoptosis resistance. Chlamydia trachomatis are major human pathogens causing ocular and sexually transmitted diseases with hundreds of millions of cases per year. Chlamydia replicate inside the host cell in a membrane bound vacuole called inclusion. The current concept on how Chlamydia communicates with the host cell during its replication is based on the identification of the host protein that interacts with Chlamydia. Here, we describe that C. trachomatis-serovar L2 and D use EphA2, a member of the largest class of human receptor tyrosine kinases, as an adherence and entry receptor that is endocytosed together with the bacteria. Cell surface EphA2 receptor is adopted by Chlamydia to function also at the inclusion to support growth and replication and to keep the infected cell in an apoptosis resistant state. Thus, we show that EphA2 is an undiscovered important surface and intracellular signaling receptor that is crucial for chlamydial infection and development.
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DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
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作者：
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DOI：
10.1073/pnas.1119592109
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2012-05-08
影响因子：
11.1
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影响因子：
3.1
作者：
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影响因子：
6.7
作者：
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DOI：
10.1111/tra.12123
发表时间：
2013-12
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
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作者：
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Huynh-Do U