Viral macro domains reverse protein ADP-ribosylation

ADP-ribosylation is a post-translational protein modification in which ADP-ribose is transferred from nicotinamide dinucleotide (NAD(+)) to specific acceptors to regulate a wide variety of cellular processes. The Macro domain is an ancient and highly evolutionary conserved protein domain widely distributed throughout all kingdoms of life, including viruses. The human TARG1/C6orf130, MacroD1 and MacroD2 proteins can reverse ADP-ribosylation by acting on ADP-ribosylated substrates through the hydrolytic activity of their Macro domain. Here, we report that the Macro domain from hepatitis E virus (HEV) serves as an ADP-ribose-protein hydrolase to remove mono-ADP-ribose (MAR, de-MARylation) and poly(ADP-ribose) chains (PAR, de-PARylation) from mono- and poly(ADP)-ribosylated proteins, respectively. The presence of the HEV helicase in cis dramatically increases the binding of the Macro domain to poly(ADP-ribose) and stimulates the de-PARylation activity. Abrogation of the latter dramatically decreases replication of a HEV sub-genomic replicon. The deMARylation activity is present in all three pathogenic (+)ssRNA virus families which carry a Macro domain: Coronaviridae (severe acute respiratory syndrome coronavirus, human coronavirus 229E), Togaviridae (venezuelan equine encephalitis virus), and Hepeviridae (HEV), indicating that it might be a significant tropism and/or pathogenic determinant.

Publication year:2016

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BOF-publication weight:2

CSS-citation score:3

Authors:International

Authors from:Higher Education

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