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.
Highlights
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
The macrodomain is encoded within nonstructural protein 3 of the coronaviruses and alphaviruses and within open reading frame 1 (ORF1) of the rubella virus and hepatitis E virus
Li et al, using a luciferase reporter, found that similar mutations in these same regions reduced luciferase activity [8,30]. These studies indicate that the Hepatitis E virus (HEV) macrodomain is likely important for virus replication, though it would be of interest to determine its impact using virus replication systems for HEV, which are limited at this time
Summary
Viral macrodomains are small protein domains of about 15–20 kDa encoded within the nonstructural proteins of several RNA viruses. Computer-assisted comparisons of RNA viruses in the early 1990s identified a conserved region of known function in the polyproteins of the Coronaviridae, Togaviridae, Matonaviridae, and Hepeviridae families which was named the “X” domain [1,2]. The “X” domain was renamed macrodomain based on the protein folding that appear to be similar to the “macro” part of the macroH2A protein. Viral macrodomains were originally shown to have ADP-ribose-1”-phosphatase activity, removing phosphate from ADP-ribose-1”-phosphate. More recently, it has been demonstrated that they have hydrolase activity that removes ADP-ribose from proteins (Figure 1) [8,9]
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