Viruses from the Coronaviridae, Togaviridae, and Hepeviridae families all contain genes that encode a conserved protein domain, called a macrodomain; however, the role of this domain during infection has remained enigmatic. The recent discovery that mammalian macrodomain proteins enzymatically remove ADP-ribose, a common post-translation modification, from proteins has led to an outburst of studies describing both the enzymatic activity and function of viral macrodomains. These new studies have defined these domains as de-ADP-ribosylating enzymes, which indicates that these viruses have evolved to counteract antiviral ADP-ribosylation, likely mediated by poly-ADP-ribose polymerases (PARPs). Here, we comprehensively review this rapidly expanding field, describing the structures and enzymatic activities of viral macrodomains, and discussing their roles in viral replication and pathogenesis. Highlights Macrodomains were discovered in Togaviruses, Coronaviruses, and the hepatitis E virus over 25 years ago. They were called the ‘X’ domain because they had no known function. About 10 years later, several macrodomain structures were determined. They consist of central β-sheets surrounded by α-helices and bind to ADP-ribose and its derivatives. They were named after the structurally homologous domain of the MacroH2A histone. Originally described as ADP-ribose-1″-phosphatases, both cellular and viral macrodomains enzymatically remove mono- and poly-ADP-ribose from proteins, supporting the notion that protein ADP-ribosylation is a component of the antiviral response. Chikungunya virus and hepatitis E virus macrodomains are critical for replication, while the Coronavirus macrodomain both blocks the innate immune response and separately promotes in vivo replication.
【저자키워드】 Pathogenesis, Replication, Coronaviridae, interferon (IFN), macrodomain, ADP-ribosylation, Togaviridae, Hepeviridae, poly-ADP-ribose polymerase (PARP),