哈兽研郑永辉研究员课题组发现抗流感病毒天然免疫新机制
近日，中国农业科学院哈尔滨兽医研究所发现了病毒激活天然免疫的新机制，相关研究成果以题为"Innate sensing of influenza A virus hemagglutinin glycoproteins by the host endoplasmic reticulum (ER) stress pathway triggers a potent antiviral response via ER-associated protein degradation"发表于病毒学权威期刊《病毒学杂志（Journal of Virology）》。
天然免疫系统通过其特有的模式识别受体(PRR)，来识别病原相关模式(PAMP)分子，是人类生来就有的抵抗感染的第一道防线，具有作用范围广、反应快等特点。目前已知的病毒PAMP是各种核酸类分子，其它病毒分子是否能被识别并激活天然免疫尚不清楚，因此，相关研究是免疫学中一个非常活跃的领域。
在郑永辉研究员指导下，王斌博士与密歇根州立大学Dylan Frabutt发现，流感病毒囊膜糖蛋白(HA)是一种新型的PAMP。囊膜糖蛋白是病毒识别并感染宿主细胞的唯一工具，在感染过程中起决定性作用。该研究发现HA在病毒感染过程中能高效表达，进而引起感染细胞内质网应激反应；而细胞为了维持自身的稳态，通过内质网相关蛋白降解通路（ERAD）将HA蛋白降解并抑制病毒复制。进一步研究发现，EDEM1、EDEM2和ERManI这三种I-型α-甘露糖苷酶介导了HA蛋白的降解，并在抑制病毒复制过程中发挥核心作用。以上研究表明内质网应激反应具有天然抗病毒功能，其激活过程是通过识别病毒囊膜糖蛋白来实现。
本研究是继该研究小组在艾滋病病毒和埃博拉病毒研究中取得相关成果后，在病毒天然免疫研究领域中获得的又一重要发现，为免疫学的进一步发展提供了理论依据。
Abstract:
Innate immunity provides an immediate defense against infection after host cells sense “danger” signals from microbes. Endoplasmic reticulum (ER) stress arises from accumulation of misfolded/unfolded proteins when protein load overwhelms the ER folding capacity, which activates the unfolded protein response (UPR) to restore the ER homeostasis. Here, we show that a mechanism for antiviral innate immunity is triggered after the ER stress pathway senses viral glycoproteins. When hemagglutinin (HA) glycoproteins from influenza A virus (IAV) are expressed in cells, ER stress is induced, resulting in rapid HA degradation via proteasomes. The ER-associated protein degradation (ERAD) pathway, an important UPR function for destruction of aberrant proteins, mediates HA degradation. Three class I α-mannosidases were identified to play a critical role in the degradation process, including EDEM1, EDEM2, and ERManI. HA degradation requires either ERManI enzymatic activity or EDEM1/EDEM2 enzymatic activity, when ERManI is not expressed, indicating that demannosylation is a critical step for HA degradation. Silencing of EDEM1, EDEM2, and ERManI strongly increases HA expression and promotes IAV replication. Thus, the ER stress pathway senses influenza HA as “non-self” or misfolded protein, and sorts HA to ERAD for degradation, resulting in inhibition of IAV replication.
本文来源：中国农业科学院哈尔滨兽医研究所
本文编辑：蒲公英