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引起人类呼吸道感染的冠状病毒已多达5种.冠状病毒与宿主相互作用决定了其致病性和免疫特性.冠状病毒感染后宿主会立即启动抗病毒天然免疫反应,而人类冠状病毒往往会编码特定蛋白逃逸或抑制宿主的天然免疫反应.NL63冠状病毒是一种新型人类冠状病毒,其非结构蛋白nsp3编码2个木瓜样蛋白酶(PLP)核心结构域PLP1和PLP2.前期研究发现,人类冠状病毒PLP2是一种病毒编码的去泛素化酶(DUB),但是对其DUB特性和功能还不清楚.研究发现,NL63冠状病毒PLP1和PLP2两个核心结构域中只有PLP2具有DUB活性,而且,PLP2的DUB活性对K48和K63连接的多聚泛素化修饰不表现明显特异性.同时,蛋白酶活性催化位点C1678和H1836突变后对其DUB活性有明显抑制作用,而蛋白酶活性催化位点D1849突变后对DUB活性无影响.其次,PLP2而非PLP1核心结构域能够明显抑制仙台病毒和重要信号蛋白(RIG-I、ERIS/STING/MITA)激活的干扰素表达,表明PLP2是一种冠状病毒编码的干扰素拮抗剂,而且PLP2的干扰素拮抗作用不完全依赖其蛋白酶活性.机制研究表明,PLP2能够与干扰素表达通路中的重要调节蛋白RIG-I和ERIS发生相互作用,通过对RIG-I和ERIS的去泛素化负调控宿主抗病毒天然免疫反应.此外,PLP2除利用DUB活性抑制干扰素表达外,很可能存在不依赖自身催化活性的其他组分共同抑制干扰素的产生.以上研究对阐明人类新发冠状病毒免疫和致病机理以及抗病毒药物研发具有重要参考价值。
Coronaviruses that cause respiratory infections in humans have as many as 5. Coronaviruses interact with the host to determine its pathogenicity and immune properties.After infection with a coronavirus, the host immediately initiates an antiviral innate immune response, and the human coronavirus tends to encode Specific protein escapes or inhibits the host’s innate immune response.NL63 coronavirus is a novel human coronavirus whose nonstructural protein nsp3 encodes two papain-like (PLP) core domains PLP1 and PLP2.Previous studies found that human coronavirus PLP2 is a virus-encoded deubiquitinating enzyme (DUB), but its DUB properties and functions are unclear.Studies have found that only PLP2 has the activity of DUB2 in the two core domains of NLPV coronavirus PLP1 and PLP2, DUB activity of PLP2 did not show significant specificity for the polyubiquitination of K48 and K63.At the same time, mutants of C1678 and H1836 with protease activity had obvious inhibitory effect on DUB activity, whereas protease activity of D1849 Mutation had no effect on DUB activity.Secondly, PLP2, but not the PLP1 core domain, significantly inhibited Sendai virus and important signaling proteins (RIG-I, ERIS / STING / MITA) Live interferon expression indicates that PLP2 is a coronavirus-encoded interferon antagonist and that the antagonist action of PLP2 on interferon is not completely dependent on its protease activity. Mechanistic studies have shown that PLP2 interacts with important regulatory proteins in the interferon expression pathway RIG-I interacts with ERIS and negatively regulates host innate antiviral innate immune responses by de-ubiquitination of RIG-I and ERIS. In addition, PLP2 may inhibit the expression of interferon by using DUB activity, Activity of other components together inhibit interferon production.The above study to elucidate the new human coronavirus immunization and pathogenesis and development of antiviral drugs has important reference value.