title: Viral Macro Domains Reverse Protein ADP-Ribosylation.
abstract: ADP-ribosylation is a posttranslational protein modification in which ADP-ribose is transferred from NAD(+) to specific acceptors to regulate a wide variety of cellular processes. The macro domain is an ancient and highly evolutionarily 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 domains. Here, we report that the macro domain from hepatitis E virus (HEV) serves as an ADP-ribose-protein hydrolase for mono-ADP-ribose (MAR) and poly(ADP-ribose) (PAR) chain removal (de-MARylation and de-PARylation, respectively) 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 an HEV subgenomic replicon. The de-MARylation activity is present in all three pathogenic positive-sense, single-stranded RNA [(+)ssRNA] virus families which carry a macro domain: Coronaviridae (severe acute respiratory syndrome coronavirus and human coronavirus 229E), Togaviridae (Venezuelan equine encephalitis virus), and Hepeviridae (HEV), indicating that it might be a significant tropism and/or pathogenic determinant.
  
  
  
  Protein ADP-ribosylation is a covalent posttranslational modification regulating cellular protein activities in a dynamic fashion to modulate and coordinate a variety of cellular processes. Three viral families, Coronaviridae, Togaviridae, and Hepeviridae, possess macro domains embedded in their polyproteins. Here, we show that viral macro domains reverse cellular ADP-ribosylation, potentially cutting the signal of a viral infection in the cell. Various poly(ADP-ribose) polymerases which are notorious guardians of cellular integrity are demodified by macro domains from members of these virus families. In the case of hepatitis E virus, the adjacent viral helicase domain dramatically increases the binding of the macro domain to PAR and simulates the demodification activity.
authors.affiliation: CNRS, AFMB UMR 7257, Marseille, France Aix-Marseille Université, AFMB UMR 7257, Marseille, France.
authors.forename: Changqing
authors.initials: C
authors.lastname: Li
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Debing
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Gytis
authors.initials: G
authors.lastname: Jankevicius
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ahel
authors.affiliation: CNRS, AFMB UMR 7257, Marseille, France Aix-Marseille Université, AFMB UMR 7257, Marseille, France bruno.coutard@afmb.univ-mrs.fr bruno.canard@afmb.univ-mrs.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Coutard
authors.affiliation: CNRS, AFMB UMR 7257, Marseille, France Aix-Marseille Université, AFMB UMR 7257, Marseille, France bruno.coutard@afmb.univ-mrs.fr bruno.canard@afmb.univ-mrs.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Canard
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D016752:Hepatitis E virus / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D020815:Polyproteins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D020815:Polyproteins; D014764:Viral Proteins; D000246:Adenosine Diphosphate Ribose