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EphA2 phosphorylates NLRP3 and inhibits inflammasomes in airway epithelial cells.
EMBO Reports ( IF 7.7 ) Pub Date : 2020-04-30 , DOI: 10.15252/embr.201949666
Ao Zhang 1, 2 , Junji Xing 2 , Tianliang Xia 1 , Hua Zhang 3 , Mingli Fang 2, 4 , Shibing Li 1 , Yong Du 2 , Xian C Li 2, 5 , Zhiqiang Zhang 2, 5 , Mu-Sheng Zeng 1
Affiliation  

Inflammasomes are intracellular complexes that form in the cytosol of inflammatory cells. NLRP 3 is one of the sensor proteins in the complex that can recognize a wide variety of stimuli ranging from microbial components to environmental particulates. Here, we report that in mouse airway epithelial cells (AEC s), inflammasome activation is inhibited by EphA2, a member of the transmembrane tyrosine kinase receptor family, via tyrosine phosphorylation of NLRP 3 in a model of reovirus infection. We find that EphA2 depletion markedly enhances interleukin‐1β (IL ‐1β) and interleukin‐18 (IL ‐18) production in response to the virus. EphA2 −/− mice show stronger inflammatory infiltration and enhanced inflammasome activation upon viral infection, and aggravated asthma symptoms upon ovalbumin (ova) induction. Mechanistically, EphA2 binds to NLRP 3 and induces its phosphorylation at Tyr132, thereby interfering with ASC speck formation and blocking the activation of the NLRP 3‐inflammasome. These data demonstrate that reovirus employs EphA2 to suppress inflammasome activation in AEC s and that EphA2 deficiency causes a pathological exacerbation of asthma in an ova‐induced asthma model.

中文翻译:

EphA2 磷酸化 NLRP3 并抑制气道上皮细胞中的炎症小体。

炎性体是在炎性细胞的胞质溶胶中形成的细胞内复合物。NLRP 3 是复合物中的一种传感器蛋白,可以识别从微生物成分到环境颗粒的各种刺激。在这里,我们报告在呼肠孤病毒感染模型中,通过 NLRP 3 的酪氨酸磷酸化,跨膜酪氨酸激酶受体家族的成员 EphA2 可抑制小鼠气道上皮细胞 (AEC) 的炎症小体活化。我们发现 EphA2 消耗显着增强了白细胞介素-1β (IL-1β) 和白细胞介素-18 (IL-18) 对病毒的反应。EphA2 -/-小鼠在病毒感染后表现出更强的炎症浸润和增强的炎症小体活化,并在卵清蛋白(ova)诱导后加重哮喘症状。从机制上讲,EphA2 与 NLRP 3 结合并诱导其在 Tyr132 处的磷酸化,从而干扰 ASC 斑点的形成并阻断 NLRP 3 炎性体的激活。这些数据表明呼肠孤病毒利用 EphA2 来抑制 AEC 中炎症小体的激活,并且 EphA2 缺乏会在卵子诱导的哮喘模型中导致哮喘的病理恶化。
更新日期:2020-07-03
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