Zinc-finger PARP Proteins ADP-ribosylate Alphaviral Proteins and Are Required for Interferon-γ-mediated Antiviral Immunity

Overview

Journal Sci Adv

Date 2025 Jan 31

PMID 39888989

Authors

Andrew P Ryan

Sofia E Delgado-Rodriguez

Matthew D Daugherty

Affiliations

Soon will be listed here.

Abstract

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.

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