The Viral Macrodomain Counters Host Antiviral ADP-Ribosylation

Abstract

Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune responses to virus infection. ADP-ribose is covalently attached to target proteins by poly-ADP-ribose polymerases (PARPs), using nicotinamide adenine dinucleotide (NAD+) as a substrate. This modification can have a wide variety of effects on proteins including alteration of enzyme activity, protein-protein interactions, and protein stability. Several PARPs are induced by interferon (IFN) and are known to have antiviral properties, implicating ADP-ribosylation in the host defense response and suggesting that viral macrodomains may counter this response. Recent studies have demonstrated that viral macrodomains do counter the innate immune response by interfering with PARP-mediated antiviral defenses, stress granule formation, and pro-inflammatory cytokine production. Here, we will describe the known functions of the viral macrodomains and review recent literature demonstrating their roles in countering PARP-mediated antiviral responses.

Keywords: ADP-ribose; ADP-ribosylation; PARPs; RNA virus; alphaviruses; coronaviruses; hepatitis E virus; macrodomain; stress granule.

Figure 1

A schematic representation of the ADP-ribosylation and de-ADP-ribosylation by the viral macrodomains: The crystal structures of the poly-ADP-ribose polymerase (PARP)-12 protein [10] were downloaded from the protein data bank (PDB) (doi:10.2210/pdb2PQF/pdb), and the Venezuelan equine encephalitis virus (VEEV) macrodomain structure [11] was downloaded from the PDB (doi:10.2210/pdb5mqx/pdb).

Figure 2

Sequence alignment of the amino acid sequences of various viral macrodomains from coronaviruses, alphaviruses, rubellavirus, and hepatitis E virus: The human macroD2 protein sequence was included for comparison. Sequences of viral and human macrodomains were alignment using CLC Genomics Workbench software. Arrows indicate residues that are discussed in the text.

Figure 3

Phylogenetic tree of the viral macrodomains proteins sequences constructed with the neighbor joining method using Geneious Bioinformatics software.

Figure 4

The crystal structure of the VEEV macrodomain protein [11] was downloaded from the PDB (doi:10.2210/pdb5mqx/pdb): Highlighted residues are D21 (blue, D20 in chikungunya virus (CHIKV)); N35 (black, N34 in CHIKV); G33 (red, G32 in CHIKV); T112 (yellow, T111 in CHIKV); and F115 (purple, Y114 in CHIKV). ADP-ribose (ADPR) is also shown.