PMID:28150709

Citation	Eckei, L, Krieg, S, Bütepage, M, Lehmann, A, Gross, A, Lippok, B, Grimm, AR, Kümmerer, BM, Rossetti, G, Lüscher, B and Verheugd, P (2017) The conserved macrodomains of the non-structural proteins of Chikungunya virus and other pathogenic positive strand RNA viruses function as mono-ADP-ribosylhydrolases. Sci Rep 7:41746
Abstract	Human pathogenic positive single strand RNA ((+)ssRNA) viruses, including Chikungunya virus, pose severe health problems as for many neither efficient vaccines nor therapeutic strategies exist. To interfere with propagation, viral enzymatic activities are considered potential targets. Here we addressed the function of the viral macrodomains, conserved folds of non-structural proteins of many (+)ssRNA viruses. Macrodomains are closely associated with ADP-ribose function and metabolism. ADP-ribosylation is a post-translational modification controlling various cellular processes, including DNA repair, transcription and stress response. We found that the viral macrodomains possess broad hydrolase activity towards mono-ADP-ribosylated substrates of the mono-ADP-ribosyltransferases ARTD7, ARTD8 and ARTD10 (aka PARP15, PARP14 and PARP10, respectively), reverting this post-translational modification both in vitro and in cells. In contrast, the viral macrodomains possess only weak activity towards poly-ADP-ribose chains synthesized by ARTD1 (aka PARP1). Unlike poly-ADP-ribosylglycohydrolase, which hydrolyzes poly-ADP-ribose chains to individual ADP-ribose units but cannot cleave the amino acid side chain - ADP-ribose bond, the different viral macrodomains release poly-ADP-ribose chains with distinct efficiency. Mutational and structural analyses identified key amino acids for hydrolase activity of the Chikungunya viral macrodomain. Moreover, ARTD8 and ARTD10 are induced by innate immune mechanisms, suggesting that the control of mono-ADP-ribosylation is part of a host-pathogen conflict.
Links	PubMed PMC5288732 Online version:10.1038/srep41746
Keywords	Catalysis; Chikungunya virus/genetics; Chikungunya virus/metabolism; Conserved Sequence; Enzyme Activation; Humans; Hydrolysis; Models, Molecular; Mutation; Poly Adenosine Diphosphate Ribose/metabolism; Poly(ADP-ribose) Polymerases/chemistry; Poly(ADP-ribose) Polymerases/genetics; Poly(ADP-ribose) Polymerases/metabolism; Protein Conformation; Protein Interaction Domains and Motifs; Proto-Oncogene Proteins/chemistry; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; RNA Viruses/genetics; RNA Viruses/metabolism; Substrate Specificity; Viral Nonstructural Proteins/chemistry; Viral Nonstructural Proteins/genetics; Viral Nonstructural Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
EEVVT:POLN	enables	GO:0047407: ADP-ribosyl-[dinitrogen reductase] hydrolase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete

References

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