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.
Highlights
The first group are able to iteratively transfer multiple ADPr units onto their substrates resulting in the formation of long branched ADPr polymers (PAR)
IFNαrepresents the first line response against invading viruses and triggers a robust and complex antiviral cellular program by inducing more than 300 IFN-stimulated genes (ISGs)[45,46]. These two mono-ADP-ribosyltransferase diphtheria toxin-like (ARTD) are ISGs, consistent with previous studies demonstrating that the expression of these genes is induced in response to pathogens[3,17]
The induction of ARTD8 and ARTD10 as measured in time-course experiments occurred with some delay suggesting that they are not direct IFNα/ISGF3 (STAT1-STAT2-IRF9 heterotrimeric complex) target genes or that the cooperativity with additional signals is relevant for induced expression
Summary
The first group (including ARTD1/2/5/6) are able to iteratively transfer multiple ADPr units onto their substrates resulting in the formation of long branched ADPr polymers (PAR). ARTD13 interferes with viral RNA translation and replication by interaction with viral RNA through its four CCCH-type zinc fingers thereby promoting its degradation[3] Taken together these findings strongly imply important functions for ARTD family members in innate immunity and suggest that ADP-ribosylation and its functional consequences contribute to the resolution of host-pathogen conflicts. The fact that macrodomains are conserved domains of non-structural proteins of some positive single strand RNA ((+) ssRNA) viruses provides further evidence for a function of ADP-ribosylation in innate immunity[24,25] These ((+) ssRNA) viruses include members of the alphavirus genus such as Chikungunya virus (CHIKV), O’nyong’nyong virus (ONNV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV); members of the orthohepevirus genus among them Hepatitis E virus (HEV), as well as members of the alphacoronavirus genus, to which Feline Infectious Peritonitis virus (FIPV), a mutant of Feline coronavirus, belongs. The mouse hepatitis virus macrodomain promotes virulence in mice38. vMDs seem to be critical for viral pathogenesis and evasion of the host immune response
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