Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis

Anthony R Fehr; Gytis Jankevicius; Ivan Ahel; Stanley Perlman

doi:10.1016/j.tim.2017.11.011

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Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis

Journal article

Open access

Peer reviewed

Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis

Anthony R Fehr, Gytis Jankevicius, Ivan Ahel and Stanley Perlman

Trends in Microbiology, Vol.26(7), pp.598-610

07/2018

DOI: 10.1016/j.tim.2017.11.011

PMCID: PMC6003825

PMID: 29268982

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Abstract

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. 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.

replication

pathogenesis

poly-ADP-ribose polymerase (PARP)

macrodomain

Togaviridae

Hepeviridae

Coronaviridae

interferon (IFN)

ADP-ribosylation

Details

Title: Subtitle: Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis
Creators: Anthony R Fehr - University of Iowa, Department of Microbiology and Immunology, Iowa City, IA 52242, USA
Gytis Jankevicius - Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
Ivan Ahel - Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
Stanley Perlman - University of Iowa, Department of Microbiology and Immunology, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Trends in Microbiology, Vol.26(7), pp.598-610
DOI: 10.1016/j.tim.2017.11.011
PMID: 29268982
PMCID: PMC6003825
NLM abbreviation: Trends Microbiol
ISSN: 0966-842X
eISSN: 1878-4380
Publisher: Elsevier Ltd
Grant note: name: Wellcome Trust grant, award: 101794; name: Cancer Research UK grant, award: C35050/A22284; name: National Institute of Health, award: R01 AI129269, RO1 NS36592, P01 AI060699
Language: English
Date published: 07/2018
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9983777349302771

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