The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.
J Virol. 2014 Apr;88(7):3664-77. doi: 10.1128/JVI.03013-13. Epub 2014 Jan 15.
Tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) is a pivotal intracellular mediator of signaling pathways downstream of TNFR1 and -2 with known pro- and antiviral effects. We investigated its role in the replication of the prototype poxvirus vaccinia virus (VACV). Loss of TRAF2 expression, either through small interfering RNA treatment of HeLa cells or through genetic knockout in murine embryonic fibroblasts (MEFs), led to significant reductions in VACV growth following low-multiplicity infection. In single-cycle infections, there was delayed production of both early and late VACV proteins as well as accelerated virus-induced alterations to cell morphology, indicating that TRAF2 influences early stages of virus replication. Consistent with an early role, uncoating assays showed normal virus attachment but delayed virus entry in the absence of TRAF2. Although alterations to c-Jun N-terminal kinase (JNK) signaling were apparent in VACV-infected TRAF2(-/-) MEFs, treatment of wild-type cells with a JNK inhibitor did not affect virus entry. Instead, treatment with an inhibitor of endosomal acidification greatly reduced virus entry into TRAF2(-/-) MEFs, suggesting that VACV is reliant on the endosomal route of entry in the absence of TRAF2. Thus, TRAF2 is a proviral factor for VACV that plays a role in promoting efficient viral entry, most likely via the plasma membrane.
Tumor necrosis factor receptor-associated factors (TRAFs) are key facilitators of intracellular signaling with roles in innate and adaptive immunity and stress responses. We have discovered that TRAF2 is a proviral factor in vaccinia virus replication in both HeLa cells and mouse embryonic fibroblasts and that its influence is exercised through promotion of efficient virus entry.
肿瘤坏死因子受体（TNFR）相关因子 2（TRAF2）是 TNFR1 和 -2 下游信号通路的关键细胞内介质，具有已知的促病毒和抗病毒作用。我们研究了它在原型痘病毒牛痘病毒（VACV）复制中的作用。通过 HeLa 细胞的小干扰 RNA 处理或通过鼠胚胎成纤维细胞（MEF）中的基因敲除来丧失 TRAF2 表达，导致低倍数感染后 VACV 生长显著减少。在单周期感染中，早期和晚期 VACV 蛋白的产生均延迟，并且病毒诱导的细胞形态改变加速，表明 TRAF2 影响病毒复制的早期阶段。与早期作用一致，非包被测定显示正常的病毒附着，但在缺乏 TRAF2 的情况下病毒进入延迟。尽管在 VACV 感染的 TRAF2（-/-）MEF 中明显改变了 c-Jun N-末端激酶（JNK）信号，但用 JNK 抑制剂处理野生型细胞不会影响病毒进入。相反，用内体酸化抑制剂处理大大减少了 TRAF2（-/-）MEF 中的病毒进入，表明在缺乏 TRAF2 的情况下，VACV 依赖于内体进入途径。因此，TRAF2 是 VACV 的促病毒因子，在促进有效的病毒进入中起作用，可能通过质膜。
肿瘤坏死因子受体相关因子（TRAFs）是细胞内信号转导的关键促进剂，在先天和适应性免疫以及应激反应中发挥作用。我们发现 TRAF2 是 HeLa 细胞和鼠胚胎成纤维细胞中 VACV 复制的促病毒因子，其影响是通过促进有效的病毒进入来发挥的。
