The conserved macrodomains of the non-structural proteins of Chikungunya virus and other pathogenic positive strand RNA viruses function as mono-ADP-ribosylhydrolases

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 addres...

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Published in:Scientific reports 2017-02, Vol.7 (1), p.41746-41746, Article 41746
Main Authors: Eckei, Laura, Krieg, Sarah, Bütepage, Mareike, Lehmann, Anne, Gross, Annika, Lippok, Barbara, Grimm, Alexander R, Kümmerer, Beate M, Rossetti, Giulia, Lüscher, Bernhard, Verheugd, Patricia
Format: Article
Language:English
Subjects:
ADP-ribosylation
Amino acids
Catalysis
Chikungunya virus
Chikungunya virus - genetics
Chikungunya virus - metabolism
Conserved Sequence
DNA repair
Enzyme Activation
Humans
Hydrolase
Hydrolysis
Models, Molecular
Mutation
Pathogens
Poly Adenosine Diphosphate Ribose - metabolism
Poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerases - chemistry
Poly(ADP-ribose) Polymerases - genetics
Poly(ADP-ribose) Polymerases - metabolism
Post-translation
Protein Conformation
Protein Interaction Domains and Motifs
Proto-Oncogene Proteins - chemistry
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Ribose
Ribosylation
RNA viruses
RNA Viruses - genetics
RNA Viruses - metabolism
Structural proteins
Substrate Specificity
Transcription
Translation
Viral Nonstructural Proteins - chemistry
Viral Nonstructural Proteins - genetics
Viral Nonstructural Proteins - metabolism
Viruses
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep41746