Laboratory of Virology and Infectious Disease, The Rockefeller University, 1230 York Ave., New York, NY 10065, USA.
J Virol. 2010 May;84(9):4504-12. doi: 10.1128/JVI.02018-09. Epub 2010 Feb 24.
The zinc finger antiviral protein (ZAP) is a host factor with potent antiviral activity when overexpressed in cells. ZAP blocks replication of the prototype alphavirus Sindbis virus (SINV) at a step at or before translation of the incoming viral genome. The mechanism of ZAP anti-SINV activity and the determinants of its antiviral function, however, have not been defined. Here, we have identified a dominant negative inhibitor of human ZAP. Rat ZAP with a cysteine-to-arginine mutation at position 88 (rZAPC88R), previously reported as a nonfunctional form of ZAP, increases SINV growth in cells. These results led us to discover a previously undetectable pool of endogenous functional ZAP within human cells. Investigation of the mechanism of dominant negative inhibition, combined with a comprehensive mutational analysis of the antiviral factor, revealed that homotypic associations are required for ZAP function in limiting SINV propagation.
锌指抗病毒蛋白 (ZAP) 是一种宿主因子，在细胞中过表达时具有很强的抗病毒活性。ZAP 可在翻译病毒基因组之前或在翻译病毒基因组时阻止原型甲病毒辛德毕斯病毒 (SINV) 的复制。然而，ZAP 抗 SINV 活性的机制及其抗病毒功能的决定因素尚未确定。在这里，我们已经鉴定出一种人 ZAP 的显性负抑制剂。先前报道的第 88 位半胱氨酸到精氨酸突变的大鼠 ZAP (rZAPC88R) 增加了细胞中 SINV 的生长。这些结果导致我们在人细胞内发现了以前无法检测到的内源性功能性 ZAP 池。对显性负抑制机制的研究，结合对抗病毒因子的全面突变分析，揭示了同源相互作用是 ZAP 限制 SINV 传播功能所必需的。
