PDF(Pubmed)
Abstract：
Enteroviruses are the causative agents associated with several human and animal diseases, posing a significant threat to human and animal health. As one of the host immune defense strategies, innate immunity plays a crucial role in defending against invading pathogens, where the host utilizes a variety of mechanisms to inhibit or eliminate the pathogen. Here, we report a new strategy for the host to repress enterovirus replication by the 78 kDa glucose-regulated protein (GRP78), also known as heat shock protein family A member 5 (HSPA5). The GRP78 recognizes the EV-encoded RNA-dependent RNA polymerases (RdRPs) 3D protein and interacts with the nuclear factor kappa B kinase complex (CHUK) and subunit beta gene (IKBKB) to facilitate the phosphorylation and nuclear translocation of NF-κB, which induces the production of inflammatory factors and leads to a broad inhibition of enterovirus replication. These findings demonstrate a new role of GRP78 in regulating host innate immunity in response to viral infection and provide new insights into the mechanism underlying enterovirus replication and NF-κB activation.IMPORTANCEGRP78 is known as a molecular chaperone for protein folding and plays a critical role in maintaining protein folding and participating in cell proliferation, cell survival, apoptosis, and metabolism. However, the functions of GRP78 to participate in enterovirus genome replication and innate immune responses are rarely documented. In this study, we explored the functions of the EV-3D-interacting protein GRP78 and found that GRP78 inhibits enterovirus replication by activating NF-κB through binding to EV-F 3D and interacting with the NF-κB signaling molecules CHUK/IKBKB. This is the first report that GRP78 interacts with CHUK/IKBKB to activate the NF-κB signaling pathway, which leads to the expression of the proinflammatory cytokines and inhibition of enterovirus replication. These results demonstrate a unique mechanism of virus replication regulation by GRP78 and provide insights into the prevention and treatment of viral infections.
摘要：
肠道病毒是与几种人类和动物疾病相关的病原体，对人类和动物健康构成重大威胁。作为宿主免疫防御策略之一,先天免疫在抵御入侵病原体中起着至关重要的作用，其中宿主利用各种机制来抑制或消除病原体。这里,我们报道了宿主通过78kDa葡萄糖调节蛋白（GRP78）抑制肠道病毒复制的新策略，也称为热休克蛋白家族A成员5(HSPA5)。GRP78识别EV编码的RNA依赖性RNA聚合酶（RdRPs）3D蛋白，并与核因子κB激酶复合物（CHUK）和亚基β基因（IKBKB）相互作用，以促进NF-κB的磷酸化和核易位，诱导炎症因子的产生，并导致肠道病毒复制的广泛抑制。这些发现证明了GRP78在调节宿主对病毒感染的先天免疫中的新作用，并为肠道病毒复制和NF-κB激活的潜在机制提供了新的见解。IMPORTANCEGRP78被认为是蛋白质折叠的分子伴侣，在维持蛋白质折叠和参与细胞增殖中起着至关重要的作用。细胞存活,凋亡，和新陈代谢。然而,GRP78参与肠道病毒基因组复制和先天免疫应答的功能鲜有记载.在这项研究中,我们探索了EV-3D相互作用蛋白GRP78的功能，发现GRP78通过与EV-F3D结合并与NF-κB信号分子CHUK/IKBKB相互作用而激活NF-κB，从而抑制肠道病毒的复制。这是首次报道GRP78与CHUK/IKBKB相互作用激活NF-κB信号通路，导致促炎细胞因子的表达和肠道病毒复制的抑制。这些结果证明了GRP78调节病毒复制的独特机制，并为预防和治疗病毒感染提供了见解。
