Chlamydia repurposes the actin-binding protein EPS8 to disassemble epithelial tight junctions and promote infection.
Chlamydia repurposes the actin-binding protein EPS8 to disassemble epithelial tight junctions and promote infection.
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DOI：
10.1016/j.chom.2022.10.013
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发表时间：
2022-12-14
影响因子：
30.3
通讯作者：
Valdivia, Raphael H.
中科院分区：
文献类型：
--
作者：
Dolat, Lee;Carpenter, Victoria K.;Chen, Yi-Shan;Suzuki, Michitaka;Smith, Erin P.;Kuddar, Ozge;Valdivia, Raphael H.
侵入性微生物病原体经常破坏上皮屏障，但用于拆除紧密连接的机制知之甚少。在这里，我们表明，专性病原体沙眼衣原体使用的效应蛋白TepP瞬时拆卸紧密连接在感染早期。TepP改变参与细胞骨架调节的宿主蛋白的酪氨酸磷酸化状态，包括丝状肌动蛋白结合蛋白EPS8。我们确定TepP和EPS8是重塑紧密连接所必需的，并且随后上皮屏障功能的破坏促进了继发性侵袭事件。EPS8的基因缺失使得上皮细胞和子宫内膜类器官对TepP介导的紧密连接重塑具有抗性。最后，TepP和EPS8在感染的小鼠模型中促进感染，其中TepP突变体在向上生殖道的Ascension中显示缺陷。这些发现揭示了EPS8在上皮连接解体中的非典型功能和衣原体发病机制的重要作用。Dolat等人发现，专性细胞内病原体沙眼衣原体破坏上皮细胞紧密连接以促进感染。作者确定了C.沙眼衣原体分泌的效应TepP在重新利用宿主肌动蛋白结合蛋白EPS8拆除紧密连接和促进极化上皮细胞的侵袭。
Invasive microbial pathogens often disrupt epithelial barriers, yet the mechanisms used to dismantle tight junctions are poorly understood. Here, we show that the obligate pathogen Chlamydia trachomatis uses the effector protein TepP to transiently disassemble tight junctions early during infection. TepP alters the tyrosine phosphorylation status of host proteins involved in cytoskeletal regulation, including the filamentous actin-binding protein EPS8. We determined that TepP-and EPS8 are necessary and sufficient to remodel tight junctions and that the ensuing disruption of epithelial barrier function promotes secondary invasion events. Genetic deletion of EPS8 renders epithelial cells and endometrial organoids resistant to TepP-mediated tight junction remodeling. Finally, TepP and EPS8 promote infection in murine models of infections, with TepP mutants displaying defects in ascension to the upper genital tract. These findings reveal a non-canonical function of EPS8 in the disassembly of epithelial junctions and an important role for Chlamydia pathogenesis. Dolat et al. show the obligate intracellular pathogen, Chlamydia trachomatis, disrupts epithelial tight junctions to promote infection. The authors identify a role for the C. trachomatis secreted effector TepP in repurposing the host actin-binding protein EPS8 to dismantle tight junctions and promote invasion of polarized epithelia.
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影响因子：
6.7
作者：
Chen YS;Bastidas RJ;Saka HA;Carpenter VK;Richards KL;Plano GV;Valdivia RH
通讯作者：
Valdivia RH
影响因子：
6.7
作者：
Elwell, Cherilyn A.;Ceesay, Alhaji;Kim, Jung Hwa;Kalman, Daniel;Engel, Joanne N.
通讯作者：
Engel, Joanne N.
影响因子：
6.7
作者：
Faris R;McCullough A;Andersen SE;Moninger TO;Weber MM
通讯作者：
Weber MM
影响因子：
3.1
作者：
Ghosh, Susmita;Ruelke, Elizabeth A.;Jewett, Travis J.
通讯作者：
Jewett, Travis J.
影响因子：
64.5
作者：
Coyne, CB;Bergelson, JM
通讯作者：
Bergelson, JM