Identification of a Dominant Negative Inhibitor of Human Zinc Finger Antiviral Protein Reveals a Functional Endogenous Pool and Critical Homotypic Interactions
Identification of a Dominant Negative Inhibitor of Human Zinc Finger Antiviral Protein Reveals a Functional Endogenous Pool and Critical Homotypic Interactions
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DOI：
10.1128/jvi.02018-09
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发表时间：
2010-05-01
影响因子：
5.4
通讯作者：
MacDonald, Margaret R.
中科院分区：
文献类型：
--
作者：
Law, Lok Man J.;Albin, Owen R.;MacDonald, Margaret R.
锌指抗病毒蛋白（ZAP）是一种在细胞中过表达时具有强效抗病毒活性的宿主因子。ZAP在进入的病毒基因组翻译时或之前的一个步骤阻断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，我们已经确定了人类ZAP的显性负抑制剂。在位置88处具有半胱氨酸至精氨酸突变的大鼠ZAP（rZAPC88R），先前报道为ZAP的非功能形式，增加细胞中的SINV生长。这些结果使我们发现了一个以前无法检测到的内源性功能性ZAP在人类细胞内的池。显性负抑制的机制的调查，结合全面的抗病毒因子的突变分析，揭示了同型协会所需的ZAP功能限制SINV的传播。
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.