Ryan Andrew P, Delgado-Rodriguez Sofia E, Daugherty Matthew D
Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Sci Adv. 2025 Jan 31;11(5):eadm6812. doi: 10.1126/sciadv.adm6812.
Viral manipulation of posttranslational modifications (PTMs) is critical to enable control over host defenses. Evidence suggests that one such PTM, adenosine 5'-diphosphate (ADP)-ribosylation, is important for viral replication, but the host and viral components involved are poorly understood. Here, we demonstrate that several human poly(ADP-ribose) polymerase (PARP) proteins, including the zinc-finger domain containing PARP7 (TiPARP) and PARP12, directly ADP-ribosylate the alphaviral nonstructural proteins (nsPs), nsP3 and nsP4. These same human PARP proteins inhibit alphavirus replication in a manner that can be antagonized by the ADP-ribosylhydrolase activity of the virally encoded macrodomain. Last, we find that knockdown of any of the three CCCH zinc-finger domain containing PARPs, PARP7, PARP12, or the enzymatically inactive PARP13 (ZAP/ZC3HAV1), attenuates the antiviral effects of interferon-γ on alphavirus replication. Combined with evolutionary analyses, these data suggest that zinc-finger PARPs share an ancestral antiviral function that can be antagonized by the activity of viral macrodomains, indicative of an ongoing evolutionary conflict between host ADP-ribosylation and viruses.
病毒对翻译后修饰（PTM）的操控对于控制宿主防御至关重要。有证据表明，一种这样的PTM，即5'-二磷酸腺苷（ADP）-核糖基化，对病毒复制很重要，但其中涉及的宿主和病毒成分却知之甚少。在此，我们证明了几种人类多聚（ADP-核糖）聚合酶（PARP）蛋白，包括含锌指结构域的PARP7（TiPARP）和PARP12，可直接将ADP-核糖基化修饰在甲病毒非结构蛋白（nsP）nsP3和nsP4上。同样这些人类PARP蛋白以一种可被病毒编码的巨结构域的ADP-核糖水解酶活性拮抗的方式抑制甲病毒复制。最后，我们发现敲低三种含CCCH锌指结构域的PARP蛋白中的任何一种，即PARP7、PARP12或无酶活性的PARP13（ZAP/ZC3HAV1），都会减弱干扰素-γ对甲病毒复制的抗病毒作用。结合进化分析，这些数据表明锌指PARP蛋白具有共同的祖先抗病毒功能，该功能可被病毒巨结构域的活性拮抗，这表明宿主ADP-核糖基化与病毒之间存在持续的进化冲突。
