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The Antiviral Activities of Poly-ADP-Ribose Polymerases

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The Antiviral Activities of Poly-ADP-Ribose Polymerases viruses Review The Antiviral Activities of Poly-ADP-Ribose Polymerases Mathilde Malgras 1, Magali Garcia 1,2, Clément Jousselin 1,2, Charles Bodet 1 and Nicolas Lévêque 1,2,* 1 Laboratoire Inflammation Tissus Epithéliaux et Cytokines, Université de Poitiers, 86073 Poitiers, France; [email protected] (M.M.); [email protected] (M.G.); [email protected] (C.J.); [email protected] (C.B.) 2 Laboratoire de Virologie et Mycobactériologie, CHU de Poitiers, 86021 Poitiers, France * Correspondence: nicolas.lévê[email protected]; Tel.: +33-(0)5-49-44-38-17 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: virus; PARP; antiviral; immunomodulation; viral escape mechanisms 1. Introduction Poly-adenosine diphosphate (ADP)-ribose polymerases (PARPs) are a family of en- Citation: Malgras, M.; Garcia, M.; zymes responsible for ADP-ribosylation, a reversible and transient post-translational modi- Jousselin, C.; Bodet, C.; Lévêque, N. The Antiviral Activities of fication of various target proteins including histones, enzymes, transcription factors and Poly-ADP-Ribose Polymerases. even PARPs themselves [1]. PARPs catalyze the transfer of one (mono-ADP-ribosylation or Viruses 2021, 13, 582. https:// MARylation) or more (poly-ADP-ribosylation or PARylation) ADP-ribose group(s) onto + doi.org/10.3390/v13040582 their target proteins using nicotinamide adenine dinucleotide (NAD ) as a substrate. ADP- ribosylation can drastically affect the functions of target proteins by modulating their Academic Editor: Sébastien Nisole enzymatic activity and by facilitating their ubiquitination, leading to their degradation [2]. PARPs can be found in cells from humans to bacteria and possess a highly conserved Received: 4 March 2021 C-terminal catalytic domain. Among prokaryotes, many virulence factors of pathogenic Accepted: 25 March 2021 bacteria such as diphtheria, cholera and clostridial toxins possess mono-ADP-ribose poly- Published: 30 March 2021 merase activity, causing important dysregulations of host cellular processes, which can lead to cell death [3]. In eukaryotes, PARPs have been identified in, at least, 77 species Publisher’s Note: MDPI stays neutral across five of the six eukaryotic supergroups involved in many cellular activities, such with regard to jurisdictional claims in as DNA repair or apoptosis [4]. The human genome encodes 17 PARPs, all sharing a published maps and institutional affil- highly conserved sequence in their catalytic domain called the “PARP signature motif”, a iations. characteristic secondary structure that binds NAD+. ADP-ribosylation of the target occurs on glutamate, aspartate, cysteine, arginine, serine and lysine residues [4–6]. Only five of the 17 human PARPs (PARP1, -2, -3, -5a and -5b) display PARP activity and can promote PARylation. However, most of the human PARPs (PARP6 to PARP12, PARP14, -15 and Copyright: © 2021 by the authors. -16) lack a residue necessary to elongate the ADP-ribose chain, and therefore add a single Licensee MDPI, Basel, Switzerland. ADP-ribose to the target, a process called MARylation [7]. Lastly, PARP13 is the only family This article is an open access article member with an inactive PARP catalytic domain (Table1). distributed under the terms and PARPs are divided into four subfamilies based on structural domains within the conditions of the Creative Commons protein outside of the PARP catalytic site. PARP1, -2 and -3 belong to the DNA-dependent Attribution (CC BY) license (https:// PARP subfamily. PARP7, -12 and -13 contain CCCH zinc-finger motifs able to bind RNA. creativecommons.org/licenses/by/ PARP5a and -5b, also known as tankyrases, possess protein-binding ankyrin repeats. 4.0/). Viruses 2021, 13, 582. https://doi.org/10.3390/v13040582 https://www.mdpi.com/journal/viruses Viruses 2021, 13, 582 2 of 14 Macro-PARPs, including PARP9, -14 and -15, contain two to three macrodomains, which can bind ADP-ribose or its derivatives. Finally, PARP4, -6, -8, -10, -11 and -16 remain unclassified due to the lack of characteristic domain other than the PARP signature [8]. Table 1. Overview of the 17 human Poly-adenosine diphosphate (ADP)-ribose polymerases (PARPs) including alternative names, structural characteristics, antiviral activity, if any, and targeted viruses. PARP Characteristic Name Other Names PARP Activity Antiviral Activity Viruses Targeted Subfamilies Domains Transcription and DNA-dependent EBV, HIV, KSHV, PARP1 ARTD1 PARylation BRCT, WGR replication PARPS MLV inhibition DNA-dependent PARP2 ARTD2 PARylation WGR ND ND PARPS DNA-dependent PARP3 ARTD3 PARylation WGR ND ND PARPS ARTD4 PARP4 MARylation Unclassified BRCT ND ND KIAA0177 ARTD5 TANK1 Replication PARP5a PARylation Tankyrases ANK EBV TIN1 inhibition ARTD6 Replication PARP5b TANK2 PARylation Tankyrases ANK EBV inhibition TNKL PARP6 ARTD17 MARylation Unclassified HPS ND ND Replication and ARTD14 Zinc-fingers, SINV, Rubella PARP7 MARylation CCCH PARPs translation TIPARP WWE virus, VEEV inhibition PARP8 ARTD16 MARylation Unclassified HPS ND ND PARP9 Viral protein ARTD9 BAL1 MARylation MacroPARPs Macrodomains EMCV +DTX3L degradation Transcription and replication PARP10 ARTD10 MARylation Unclassified UIM inhibition AIV, VEEV Viral protein degradation PARP11 ARTD11 MARylation Unclassified WWE ND ND Transcription and replication CHIKV, EMCV, ARTD12 Zinc-fingers, PARP12 MARylation CCCH PARPs inhibition RFVF, SINV, ZC3HDC1 WWE Viral protein VEEV, VSV degradation Replication and HIV, IAV, HBV, ZAP translation SINV, XMRV, Zinc-fingers, PARP13 ARTD13 Inactive CCCH PARPs inhibition Ebola virus, WWE ZC3HDC2 Viral RNA and Marburg virus, protein degradation MHV68 Macrodomains, PARP14 ARTD8 BAL2 MARylation MacroPARPs ND ND WWE ARTD7 PARP15 MARylation MacroPARPs Macrodomains ND ND BAL3 PARP16 ARTD15 MARylation Unclassified TMD ND ND Due to their distinct functional domains, PARPs can play various roles in the cell. PARPs act as transcription regulators through ADP-ribosylation of histones. Since ADP- ribose is negatively charged, PARylation or MARylation of histones leads to electrostatic repulsion with DNA, which allows recruitment of chromatin remodeling factors and increases gene transcription [9,10]. DNA-dependent PARPs act as DNA damage sensors involved in DNA break repair, with ADP-ribosylation at the double-stranded breaks acting as a signal, which allows the recruitment of DNA repair enzymes to the lesion site [11]. In Viruses 2021, 13, x FOR PEER REVIEW 3 of 15 can bind ADP-ribose or its derivatives. Finally, PARP4, -6, -8, -10, -11 and -16 remain un- classified due to the lack of characteristic domain other than the PARP signature [8]. Due to their distinct functional domains, PARPs can play various roles in the cell. PARPs act as transcription regulators through ADP-ribosylation of histones. Since ADP- ribose is negatively charged, PARylation or MARylation of histones leads to electrostatic repulsion with DNA, which allows recruitment of chromatin remodeling factors and in- creases gene transcription [9,10]. DNA-dependent PARPs act as DNA damage sensors in- Viruses 2021, 13, 582 3 of 14 volved in DNA break repair, with ADP-ribosylation at the double-stranded breaks acting as a signal, which allows the recruitment of DNA repair enzymes to the lesion site [11]. In cases of major DNA damage, overactivation of PARP1 can induce a depletion of the NAD+ casespool of in major the cell, DNA inhibiting damage, ATP overactivation production of and PARP1 cellular can inducemetabolism, a depletion ultimately of the NADleading+ to poolcell indeath the cell, by necrosis. inhibiting In ATP a final production example, and PARP5a cellular and metabolism, -5b bind ultimatelyand ADP-ribosylate leading to the celltelomeric death by repeat necrosis. factor In a1 final(TRF1), example, reducing PARP5a its binding and -5b ability bind andto DNA ADP-ribosylate and upregulating the telomerictelomere repeat maintenance factor 1 [12]. (TRF1), reducing its binding ability to DNA and upregulating telomereIn addition maintenance to these [12]. physiological functions, recent studies have highlighted the role of PARPsIn addition as actors to these in host physiological antiviral response. functions, In recent the context studies haveof viral highlighted infections, the PARP role ex- ofpression PARPs ascan actors be induced, in host as antiviral reported response. for PARP3, In the-4, -5a, context -5b, -7, of viral-8, -9, infections,-10, -11, -12, PARP -13, and expression-14, in cells can infected be induced, with coronaviruses as reported for[13, PARP3,14]. Some -4, PARPs -5a, -5b, are -7, considered -8, -9, -10, as -11, interferon- -12, -13, and -14, in cells infected with coronaviruses [13,14]. Some PARPs are considered as stimulated genes (ISGs) and can consequently play a key role in the regulation of the in- interferon-stimulated genes (ISGs) and can consequently play a key
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