Ge Maolin, Luo Zhen, Qiao Zhi, Zhou Yao, Cheng Xin, Geng Qibin, Cai Yanyan, Wan Pin, Xiong Ying, Liu Fang, Wu Kailang, Liu Yingle, Wu Jianguo
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; and.
Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China.
J Immunol. 2017 Nov 1;199(9):3280-3292. doi: 10.4049/jimmunol.1700376. Epub 2017 Sep 27.
Host innate immunity is crucial for cellular responses against viral infection sensed by distinct pattern recognition receptors and endoplasmic reticulum (ER) stress. Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and neurological diseases. However, the exact mechanism underlying the link between ER stress induced by EV71 infection and host innate immunity is largely unknown. In this study, we demonstrated that EV71 infection induces the homocysteine-induced ER protein (HERP), a modulator of the ER stress response which is dependent on the participation of MAVS. Virus-induced HERP subsequently stimulates host innate immunity to repress viral replication by promoting type-I IFNs (IFN-α and IFN-β) and type-III IFN (IFN-λ1) expression. Through interacting with TANK-binding kinase 1, HERP amplifies the MAVS signaling and facilitates the phosphorylation and nuclear translocation of IFN regulatory factor 3 and NF-κB to enhance the expression of IFNs, which leads to a broad inhibition of the replication of RNA viruses, including EV71, Sendai virus, influenza A virus, and vesicular stomatitis virus. Therefore, we demonstrated that HERP plays an important role in the regulation of host innate immunity in response to ER stress during the infection of RNA viruses. These findings provide new insights into the mechanism underlying the replication of RNA viruses and the production of IFNs, and also demonstrate a new role of HERP in the regulation of host innate immunity in response to viral infection.
宿主天然免疫对于细胞针对由不同模式识别受体和内质网（ER）应激所感知的病毒感染的反应至关重要。肠道病毒71型（EV71）是手足口病和神经系统疾病的病原体。然而，EV71感染诱导的ER应激与宿主天然免疫之间联系的确切机制在很大程度上尚不清楚。在本研究中，我们证明EV71感染诱导同型半胱氨酸诱导的ER蛋白（HERP），它是ER应激反应的一种调节剂，依赖于线粒体抗病毒信号蛋白（MAVS）的参与。病毒诱导的HERP随后通过促进I型干扰素（IFN-α和IFN-β）和III型干扰素（IFN-λ1）的表达来刺激宿主天然免疫以抑制病毒复制。通过与TANK结合激酶1相互作用，HERP放大MAVS信号并促进干扰素调节因子3和核因子κB的磷酸化和核转位以增强干扰素的表达，这导致对包括EV71、仙台病毒、甲型流感病毒和水疱性口炎病毒在内的RNA病毒复制的广泛抑制。因此，我们证明HERP在RNA病毒感染期间对ER应激反应的宿主天然免疫调节中起重要作用。这些发现为RNA病毒复制和干扰素产生的潜在机制提供了新的见解，并且还证明了HERP在针对病毒感染的宿主天然免疫调节中的新作用。
