Enterovirus 3C Protease Cleaves TRIM7 To Dampen Its Antiviral Activity.
Enterovirus 3C Protease Cleaves TRIM7 To Dampen Its Antiviral Activity.
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肠道病毒 3C 蛋白酶会裂解 TRIM7 以减弱其抗病毒活性。
DOI：
10.1128/jvi.01332-22
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发表时间：
2022
影响因子：
5.4
通讯作者：
Schoggins,JohnW
中科院分区：
文献类型：
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作者：
Fan,Wenchun;McDougal,MatthewB;Schoggins,JohnW
哺乳动物TRIM7是一种抗病毒蛋白，通过降解病毒2BC蛋白抑制多种人类肠道病毒。TRIM7是否被肠病毒相互靶向尚不清楚。本文报道了柯萨奇病毒B3 （CVB3）和脊髓灰质炎病毒两种肠道病毒的3C蛋白酶（3Cpro）靶向TRIM7进行切割。CVB3 3Cpro在谷氨酰胺24 （Q24）处切割TRIM7，导致截断的TRIM7由于E3泛素连接酶活性受到抑制而无法抑制CVB3。TRIM7 Q24在哺乳动物中高度保守，但有袋动物除外，有袋动物具有不受3Cpro切割的天然组氨酸（H24）。有袋动物也表达TRIM7的两种异构体，考拉的两种蛋白具有不同的抗病毒活性。较长的异构体包含一个额外的外显子，由于交替剪接位点的使用。这个额外的外显子包含一个独特的3Cpro切割位点，这表明某些肠道病毒可能已经进化到靶向有袋动物TRIM7，即使标准Q24缺失。结合表明TRIM7正在快速进化的计算分析，我们的数据提出了TRIM7可能成为肠道病毒逃避策略的目标的可能性，并且TRIM7在哺乳动物中的进化可能具有独特的抗病毒特性。肠病毒是重要的人类病原体，可引起病毒性心肌炎、胰腺炎和脑膜炎。了解宿主如何控制这些病毒以及病毒如何逃避宿主限制对于理解抗病毒免疫的基本概念和告知潜在的治疗干预措施非常重要。在这项研究中，我们证明柯萨奇病毒B3使用其病毒编码的蛋白酶靶向宿主抗病毒蛋白TRIM7进行切割，这表明病毒免疫逃避的潜在机制。此外，我们还发现TRIM7在某些哺乳动物谱系中已经进化到表达具有不同抗病毒活性和对病毒蛋白酶介导的裂解敏感的蛋白质变体。
Mammalian TRIM7 is an antiviral protein that inhibits multiple human enteroviruses by degrading the viral 2BC protein. Whether TRIM7 is reciprocally targeted by enteroviruses is not known. Here, we report that the 3C protease (3Cpro) from two enteroviruses, coxsackievirus B3 (CVB3) and poliovirus, targets TRIM7 for cleavage. CVB3 3Cpro cleaves TRIM7 at glutamine 24 (Q24), resulting in a truncated TRIM7 that fails to inhibit CVB3 due to dampened E3 ubiquitin ligase activity. TRIM7 Q24 is highly conserved across mammals, except in marsupials, which instead have a naturally occurring histidine (H24) that is not subject to 3Cpro cleavage. Marsupials also express two isoforms of TRIM7, and the two proteins from koalas have distinct antiviral activities. The longer isoform contains an additional exon due to alternate splice site usage. This additional exon contains a unique 3Cpro cleavage site, suggesting that certain enteroviruses may have evolved to target marsupial TRIM7 even if the canonical Q24 is missing. Combined with computational analyses indicating that TRIM7 is rapidly evolving, our data raise the possibility that TRIM7 may be targeted by enterovirus evasion strategies and that evolution of TRIM7 across mammals may have conferred unique antiviral properties.IMPORTANCEEnteroviruses are significant human pathogens that cause viral myocarditis, pancreatitis, and meningitis. Knowing how the host controls these viruses and how the viruses may evade host restriction is important for understanding fundamental concepts in antiviral immunity and for informing potential therapeutic interventions. In this study, we demonstrate that coxsackievirus B3 uses its virally encoded protease to target the host antiviral protein TRIM7 for cleavage, suggesting a potential mechanism of viral immune evasion. We additionally show that TRIM7 has evolved in certain mammalian lineages to express protein variants with distinct antiviral activities and susceptibilities to viral protease-mediated cleavage.