The Antiviral Activities of Poly-ADP-Ribose Polymerases

Abstract

The poly-adenosine diphosphate (ADP)-ribose polymerases (PARPs) are responsible for ADP-ribosylation, a reversible post-translational modification involved in many cellular processes including DNA damage repair, chromatin remodeling, regulation of translation and cell death. In addition to these physiological functions, recent studies have highlighted the role of PARPs in host defenses against viruses, either by direct antiviral activity, targeting certain steps of virus replication cycle, or indirect antiviral activity, via modulation of the innate immune response. This review focuses on the antiviral activity of PARPs, as well as strategies developed by viruses to escape their action.

Keywords: PARP; antiviral; immunomodulation; viral escape mechanisms; virus.

Figure 1

Direct antiviral activities of PARPs. PARP13 and PARP7 can induce exosome-mediated degradation of target viral RNAs (1). PARPs can also inhibit viral genome replication. PARP12 inhibits viral RNA transcription within the cell cytoplasm (2). PARP1 or PARP5 PARylate or directly interact with EBNA1, preventing EBNA1 binding to the OriP promoter and inhibiting Epstein–Barr virus (EBV) replication (3). PARPs directly interact with viral proteins. PARP9/DTX3L complex and PARP12 catalyze mono-ADP-ribosylation (MARylation) of viral proteins leading to their proteosomal degradation while PARP10, through binding to avian influenza virus NS1, prevents viral RNA replication. PARP13 binds already PARylated influenza A virus proteins leading to their proteosomal degradation (4). Finally, PARP7, -10, -12 and -13 are inhibitors of viral translation stopping the formation of the translation initiation complex on viral mRNA (5).

Figure 2

Indirect antiviral activities of PARPs through immunomodulation. PARP1 and PARP11-induced MARylation of the β-transducin repeat-containing protein (β-TrCP), an E3 ubiquitin ligase, promotes interferon alpha/beta receptor 1 (IFNAR1) ubiquitination and degradation (1). Concerning RNA virus sensing pathways, PARP13 overexpression enhances oligomerization of retinoic acid-inducible gene I (RIG-I) (2), which leads to robust activation of downstream antiviral signaling through the interferon regulatory factor 3 (IRF3) pathway. On the other hand, PARPs can also downregulate the antiviral defenses. PARP7 MARylates TANK-binding kinase 1 (TBK1), decreasing IRF3 activation and leading to impaired IFN production (3). Otherwise, PARP12 enhances the signaling cascade, leading to NF-κB activation, whereas PARP10 exerts negative feedback on this pathway through MARylation of NF-κB essential modulator (NEMO) (4). PARP13 mediates the degradation of several host IFN mRNAs (5), thereby acting as a negative feedback regulator of the interferon response. The PARP9–DTX3L complex is a direct binding partner of STAT-1, promoting STAT-1 phosphorylation and nuclear relocalization, thereby increasing ISG transcription and leading to amplification of the innate immune response (6). PARP14 specifically binds to STAT-6 responsive promoters (7), preventing STAT-6-mediated transcription. The inflammatory environment influences PARP9–DTX3L and PARP14 immunomodulatory properties. In the presence of the anti-inflammatory cytokine IL-4 (8), PARP14 carries out its own MARylation by an autocatalytic process that allows binding of STAT-6 and transcription activation. PARP9–DTX3L potentiates the response to IFN-γ by enhancing phosphorylation of STAT-1, whereas PARP14, by ADP-ribosylating STAT1, decreases the response while increasing phosphorylation of STAT-6, thereby promoting the anti-inflammatory response mediated by IL-4. PARP9–DTX3L can in turn inhibit MARylation of STAT-1 by PARP14.