Overlapping and Distinct Molecular Determinants Dictating the Antiviral Activities of TRIM56 against Flaviviruses and Coronavirus
Overlapping and Distinct Molecular Determinants Dictating the Antiviral Activities of TRIM56 against Flaviviruses and Coronavirus
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DOI：
10.1128/jvi.02505-14
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发表时间：
2014-12-01
影响因子：
5.4
通讯作者：
Li, Kui
中科院分区：
文献类型：
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作者：
Liu, Baoming;Li, Nan L.;Li, Kui
tripartite motif-containing （TRIM）蛋白已成为一类新的宿主抗病毒限制因子，在调节先天抗病毒反应中发挥着重要作用。在已知的70种TRIMs中，TRIM56能抑制牛病毒性腹泻病毒（黄病毒科的一种反刍动物鼠疫病毒）的复制，但对水疱性口炎病毒（VSV）（一种横纹肌病毒）无明显作用。然而，TRIM56的抗病毒谱仍未确定。特别是，TRIM56如何影响人类致病性病毒尚不清楚。同样不清楚的是控制TRIM56抗病毒活性的分子决定因素。本研究表明，TRIM56对黄热病病毒（YFV）、登革热病毒血清2型（DENV2）和人冠状病毒（HCoV） OC43的感染具有屏障作用，但对脑心肌炎病毒（EMCV）没有屏障作用。此外，通过有条件地表达各种TRIM56突变体的工程细胞系，我们证明TRIM56的抗黄病毒作用既需要位于n端RING结构域的E3连接酶活性，也需要其c端部分的完整性，而HCoV-OC43的限制仅依赖于TRIM56 E3连接酶活性。此外，TRIM56通过抑制细胞内病毒RNA积累而抑制YFV和DENV2的传播，但在病毒生命周期的后期阶段损害HCoV-OC43的感染，这表明不同的TRIM56结构域适应不同的抗病毒机制。总之，TRIM56是一种多功能抗病毒宿主因子，通过重叠和不同的分子决定因素赋予对YFV， DENV2和HCoV-OC43的抗性。我们之前报道了tripartite motif protein 56 （TRIM56）是一种反刍动物病原体牛病毒性腹泻病毒的宿主限制性因子。然而，TRIM56对人类致病性RNA病毒的影响尚不清楚。在这里，我们证明TRIM56限制了两种医学上重要的黄病毒，黄热病病毒（YFV）和登革热病毒血清2型（DENV2），以及一种人类冠状病毒HCoV-OC43，但不限制小核糖核酸病毒脑心肌炎病毒。此外，我们发现trim56介导的HCoV-OC43增殖抑制仅依赖于其E3连接酶活性，而其对YFV和DENV2的限制需要E3连接酶活性和c端部分的完整性。不同的分子决定因素似乎适应了TRIM56针对不同病毒家族所采用的不同抗病毒机制；虽然TRIM56抑制细胞内YFV/DENV2 RNA复制，但它在HCoV-OC43生命周期的后期阶段起作用。这些新发现阐明了TRIM56对正链RNA病毒的多功能性和特异性抗病毒活性的分子基础。
The tripartite motif-containing (TRIM) proteins have emerged as a new class of host antiviral restriction factors, with several demonstrating roles in regulating innate antiviral responses. Of > 70 known TRIMs, TRIM56 inhibits replication of bovine viral diarrhea virus, a ruminant pestivirus of the family Flaviviridae, but has no appreciable effect on vesicular stomatitis virus (VSV), a rhabdovirus. Yet the antiviral spectrum of TRIM56 remains undefined. In particular, how TRIM56 impacts human-pathogenic viruses is unknown. Also unclear are the molecular determinants governing the antiviral activities of TRIM56. Herein, we show that TRIM56 poses a barrier to infections by yellow fever virus (YFV), dengue virus serotype 2 (DENV2), and human coronavirus virus (HCoV) OC43 but not encephalomyocarditis virus (EMCV). Moreover, by engineering cell lines conditionally expressing various TRIM56 mutants, we demonstrated that TRIM56's antiflavivirus effects required both the E3 ligase activity that lies in the N-terminal RING domain and the integrity of its C-terminal portion, while the restriction of HCoV-OC43 relied upon the TRIM56 E3 ligase activity alone. Furthermore, TRIM56 was revealed to impair YFV and DENV2 propagation by suppressing intracellular viral RNA accumulation but to compromise HCoV-OC43 infection at a later step in the viral life cycle, suggesting that distinct TRIM56 domains accommodate differing antiviral mechanisms. Altogether, TRIM56 is a versatile antiviral host factor that confers resistance to YFV, DENV2, and HCoV-OC43 through overlapping and distinct molecular determinants.IMPORTANCEWe previously reported tripartite motif protein 56 (TRIM56) as a host restriction factor of bovine viral diarrhea virus, a ruminant pathogen. However, the impact of TRIM56 on human-pathogenic RNA viruses is unknown. Herein, we demonstrate that TRIM56 restricts two medically important flaviviruses, yellow fever virus (YFV) and dengue virus serotype 2 (DENV2), and a human coronavirus, HCoV-OC43, but not encephalomyocarditis virus, a picornavirus. Further, we show that TRIM56-mediated inhibition of HCoV-OC43 multiplication depends solely on its E3 ligase activity, whereas its restriction of YFV and DENV2 requires both the E3 ligase activity and integrity of the C-terminal portion. The differing molecular determinants appear to accommodate distinct antiviral mechanisms TRIM56 adopts to target different families of viruses; while TRIM56 curbs intracellular YFV/DENV2 RNA replication, it acts at a later step in HCoV-OC43 life cycle. These novel findings illuminate the molecular basis of the versatility and specificity of TRIM56's antiviral activities against positive-strand RNA viruses.