Institute of Virology, University of Bonn Medical Center, Bonn, Germany.
J Gen Virol. 2014 Apr;95(Pt 4):816-822. doi: 10.1099/vir.0.060988-0. Epub 2014 Jan 23.
The human zinc finger antiviral protein (hZAP) gene is spliced to yield a short (hZAP-S) and a long (hZAP-L) isoform. The long isoform possesses a poly(ADP-ribose) polymerase (PARP)-like domain in its C-terminus predicted to be inactive due to alterations in its triad motif compared with bona fide PARPs. Using Sindbis virus as prototype member of alphaviruses we confirmed that hZAP-L is a more potent inhibitor of alphaviruses than hZAP-S. Specific small interfering RNA knockdown of hZAP-L but not hZAP-S demonstrated a role of endogenous hZAP-L in restriction of alphavirus replication. Whilst single amino-acid substitutions in the triad motif of hZAP-L's PARP-like domain reduced the antiviral activity, exchange of all three triad motif residues to alanine or to the amino acids of active PARPs virtually abolished the antiviral effect. Contrary to previous assumptions, these results indicate an essential function of the PARP-like domain in hZAP-L's antiviral activity.
人类锌指抗病毒蛋白 (hZAP) 基因经过剪接，产生一个短型 (hZAP-S) 和一个长型 (hZAP-L) 异构体。长型异构体在其 C 末端具有一个多聚（ADP-核糖）聚合酶 (PARP) 样结构域，由于其三联体基序与真正的 PARPs 相比发生了改变，预计该结构域是无活性的。我们使用辛德毕斯病毒作为甲病毒的原型成员进行实验，证实 hZAP-L 比 hZAP-S 更能抑制甲病毒。特异性的 hZAP-L 小干扰 RNA 敲低而非 hZAP-S 敲低，证明内源性 hZAP-L 在限制甲病毒复制方面发挥了作用。虽然 hZAP-L 的 PARP 样结构域中的三联体基序的单个氨基酸取代降低了抗病毒活性，但将三联体基序的所有三个残基替换为丙氨酸或活性 PARPs 的氨基酸几乎完全消除了抗病毒作用。与之前的假设相反，这些结果表明 PARP 样结构域在 hZAP-L 的抗病毒活性中具有重要功能。
