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
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
复制标题
DOI：
10.1128/jvi.01690-17
复制
发表时间：
2018-01-01
影响因子：
5.4
通讯作者：
Zheng, Yong-Hui
中科院分区：
文献类型：
--
作者：
Frabutt, Dylan A.;Wang, Bin;Zheng, Yong-Hui
在宿主细胞感知到来自微生物的危险信号后，先天免疫提供了对感染的立即防御。内质网（Endoplasmic reticulum，ER）应激是由于当蛋白质负荷超过ER折叠能力时，错误折叠/未折叠蛋白质的积累，从而激活未折叠蛋白反应（Unfolded protein response，UPR）恢复ER稳态。在这里，我们表明，抗病毒的先天免疫机制后，ER应激途径感测病毒糖蛋白被触发。当来自甲型流感病毒（IAV）的血凝素（HA）糖蛋白在细胞中表达时，诱导ER应激，导致HA通过蛋白酶体快速降解。ER相关蛋白降解（ERAD）途径是破坏异常蛋白的重要UPR功能，介导HA降解。已确定三种I类α-甘露糖苷酶在降解过程中发挥关键作用，包括EDEM 1、EDEM 2和ERManI。当ERManI不表达时，HA降解需要ERManI酶活性或EDEM 1/EDEM 2酶活性，表明甘露糖基化是HA降解的关键步骤。EDEM 1、EDEM 2和ERManI的沉默强烈增加HA表达并促进IAV复制。因此，ER应激途径感测流感HA为“非自身”或错误折叠的蛋白质，并将HA分类为ERAD进行降解，从而抑制IAV的复制。重要性病毒核酸被认为是先天性抗病毒免疫应答的重要诱导物，其被多种类型的传感器感测，但其他诱导物和病毒先天免疫的传感器需要被鉴定和表征。在这里，我们使用IAV来研究宿主先天免疫是如何被激活的。我们发现IAV HA糖蛋白诱导ER应激，导致HA通过ERAD降解，从而抑制IAV复制。此外，我们已经鉴定了三种I类α-甘露聚糖酶，EDEM 1、EDEM 2和ERManI，它们在启动HA降解中起关键作用。这些蛋白质的敲低显著增加HA表达和IAV复制。这种抗病毒活性需要这些甘露聚糖酶的酶活性和联合作用。我们的研究结果表明，病毒糖蛋白诱导一个强大的先天性抗病毒反应，通过激活内质网应激途径在病毒感染。
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 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 alpha-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 "nonself" or misfolded protein and sorts HA to ERAD for degradation, resulting in inhibition of IAV replication.IMPORTANCE Viral nucleic acids are recognized as important inducers of innate antiviral immune responses that are sensed by multiple classes of sensors, but other inducers and sensors of viral innate immunity need to be identified and characterized. Here, we used IAV to investigate how host innate immunity is activated. We found that IAV HA glycoproteins induce ER stress, resulting in HA degradation via ERAD and consequent inhibition of IAV replication. In addition, we have identified three class I alpha-mannosidases, EDEM1, EDEM2, and ERManI, which play a critical role in initiating HA degradation. Knockdown of these proteins substantially increases HA expression and IAV replication. The enzymatic activities and joint actions of these mannosidases are required for this antiviral activity. Our results suggest that viral glycoproteins induce a strong innate antiviral response through activating the ER stress pathway during viral infection.