Abstract
ADP-ribosylation is a ubiquitous post-translational addition of either monomers or polymers of ADP-ribose to target proteins by ADP-ribosyltransferases, usually by interferon-inducible diphtheria toxin-like enzymes known as PARPs. While several PARPs have known antiviral activities, these activities are mostly independent of ADP-ribosylation. Consequently, less is known about the antiviral effects of ADP-ribosylation. Several viral families, including Coronaviridae, Togaviridae, and Hepeviridae, encode for macrodomain proteins that bind to and hydrolyze ADP-ribose from proteins and are critical for optimal replication and virulence. These results suggest that macrodomains counter cellular ADP-ribosylation, but whether PARPs or, alternatively, other ADP-ribosyltransferases cause this modification is not clear. Here we show that pan-PARP inhibition enhanced replication and inhibited interferon production in primary macrophages infected with macrodomain-mutant but not wild-type coronavirus. Specifically, knockdown of two abundantly expressed PARPs, PARP12 and PARP14, led to increased replication of mutant but did not significantly affect wild-type virus. PARP14 was also important for the induction of interferon in mouse and human cells, indicating a critical role for this PARP in the regulation of innate immunity. In summary, these data demonstrate that the macrodomain is required to prevent PARP-mediated inhibition of coronavirus replication and enhancement of interferon production.
Highlights
ADP-ribosylation is the post-translational covalent addition of a single or multiple subunits of ADPribose from NAD+ to a protein
Similar to results found in whole brain [50], N1347A virus replication, measured by viral genomic RNA content, was reduced compared to that of WT virus in isolated brain CD11b+ cells (S1B Fig)
Consistent with a role for ADP-ribosylation, several poly(ADP-ribose) polymerases (PARPs) were highly upregulated in these cells following infection with either WT or N1347A virus (S1C Fig)
Summary
ADP-ribosylation is the post-translational covalent addition of a single (mono-ADP-ribosylation or MARylation) or multiple (poly-ADP-ribosylation or PARylation) subunits of ADPribose from NAD+ to a protein. This process is catalyzed by intracellular poly(ADP-ribose) polymerases (PARPs) known as diphtheria toxin-like ADP-ribosyltransferases (ARTDs), extracellular cholera toxin-like ADP-ribosyltransferases (ARTCs) and some sirtuins catalyze ADP-ribosylation [1]. PARylating PARPs, such as PARP1/2 and PARP5a/b regulate several nuclear processes such as DNA repair, transcription, and Wnt pathway activation [9, 10]. Two sirtuins, SIRT4 and SIRT6, use ADP-ribosylation to inhibit glutamate dehydrogenase and promote DNA repair respectively [19, 20]
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