About: Mono-ADP-ribosylation by ARTD10 restricts Chikungunya virus replication by interfering with the proteolytic activity of nsP2

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About: Mono-ADP-ribosylation by ARTD10 restricts Chikungunya virus replication by interfering with the proteolytic activity of nsP2 Goto Sponge NotDistinct Permalink

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Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Mono-ADP-ribosylation by ARTD10 restricts Chikungunya virus replication by interfering with the proteolytic activity of nsP2
Creator	Goffinet, Christine Bütepage, Mareike Eckei, Laura Lüscher, Bernhard Verheugd, Patricia Krieg, Sarah Lippok, Pott, Fabian Verheirstraeten, Maud
Source	BioRxiv; MedRxiv
abstract	A subset of intracellular mono-ADP-ribosyltransferases diphtheria toxin-like (ARTDs, aka mono-PARPs) is induced by type I interferons. Some of these mono-ARTDs feature antiviral activity while certain RNA viruses, including Chikungunya virus (CHIKV), encode mono-ADP-ribosylhydrolases, suggesting a role for mono-ADP-ribosylation (MARylation) in host-virus conflicts. CHIKV expresses four non-structural proteins (nsP1-nsP4), with nsP3 containing a macrodomain that hydrolyzes and thereby reverses protein MARylation in vitro and in cells. This de-MARylation activity is essential as hydrolase inactivating mutations result in replication defective virus. However, the substrates of MARylation during CHIKV infection are unknown and thus it is unclear how the macrodomain contributes to virus replication and how mono-ARTD-dependent MARylation confers antiviral immunity. We identified ARTD10 and ARTD12 as restriction factors for CHIKV replication in a catalytic activity-dependent manner. CHIKV replication requires processing of the non-structural polyprotein nsP1-4 by the nsP2-encoded protease and the assembly of the four individual nsPs into a functional replication complex. Expression of ARTD10 and ARTD12 resulted in a reduction of processed nsPs. Similarly, MAR hydrolase inactive CHIKV replicon mutants revealed a decrease in processed nsPs, comparable to an nsP2 protease defective mutant. This suggested that the macrodomain contributes to nsP2 protease activity. In support, a hydrolase-deficient virus was complemented by a protease-deficient virus. We hypothesized that MARylation regulates the proteolytic function of nsP2. Indeed, we found that nsP2 is MARylated by ARTD10. This inhibited nsP2 protease activity, thereby preventing polyprotein processing and consequently virus replication. This inhibition was antagonized by the MAR hydrolase activity of nsP3. Together, our findings provide a mechanistic explanation for the need of the viral MAR hydrolase for efficient replication of CHIKV. Author Summary Infectious diseases still pose major health threats. Especially fast evolving viruses find ever new strategies to manipulate the immune response. With climate warming and increased human mobility vector-borne pathogens like Chikungunya virus (CHIKV) spread and cause world-wide epidemics. Beyond the acute phase, CHIKV patients regularly suffer from chronic rheumatism. This entails a decline in life quality and an economic burden. To date no drugs are approved and the mode of pathogenesis remains elusive. Here we describe a mechanistic function of the CHIKV nsP3 macrodomain. We found that the viral nsP2 is mono-ADP-ribosylated interfering with its auto-proteolytic function. The nsP3 macrodomain removes this modification and restores the protease activity that is essential for replication. Because macrodomains are highly conserved they might represent broad antiviral targets.
has issue date	2020-01-08(xsd:dateTime)
bibo:doi	10.1101/2020.01.07.896977
has license	biorxiv
sha1sum (hex)	00fe67432e35cea2b225647e42f5e919961087d9
schema:url	https://doi.org/10.1101/2020.01.07.896977
resource representing a document's title	Mono-ADP-ribosylation by ARTD10 restricts Chikungunya virus replication by interfering with the proteolytic activity of nsP2
schema:publication	bioRxiv
resource representing a document's body	covid:00fe67432e35cea2b225647e42f5e919961087d9#body_text
is schema:about of	named entity 'Recent' named entity 'nsP3' named entity 'replication' named entity 'defective' named entity 'activity' named entity 'acute' named entity 'health' named entity 'CHIKV' named entity 'Chikungunya virus' named entity 'life quality' named entity 'This' named entity 'hypothesized' named entity 'Expression' named entity 'CHIKV' named entity 'evolving' named entity 'intracellular' named entity 'entails' named entity 'protease' named entity 'elusive' named entity 'factors' named entity 'protease' named entity 'CHIKV' named entity 'virus' named entity 'proteolytic' named entity 'CLIMATE' named entity 'REGULATION' named entity 'DEPENDENT' named entity 'NSP1' named entity 'NON-' named entity 'FOUND' named entity 'ROLE' named entity 'CONTAINING' named entity 'EVOLVING' named entity 'manipulate' named entity 'CHIKV' named entity 'protein' named entity 'epidemics' named entity 'nsP3' named entity 'activity' named entity 'represent' named entity 'efficient' named entity 'substrates' named entity 'aka' named entity 'mechanistic' named entity 'function' named entity 'feature' named entity 'viral infections' named entity 'MAR' named entity 'strategies' named entity 'essential' named entity 'polyprotein' named entity 'With' named entity 'ADP-ribosylation' named entity 'restriction' named entity 'activity' named entity 'drugs' named entity 'protease' named entity 'virus' named entity 'viruses' named entity 'vector-borne' named entity 'hydrolyzes' named entity 'processing' named entity 'encoding' named entity 'climate warming' named entity 'human mobility' named entity 'pathogens' named entity 'CHIKV' named entity 'antiviral' named entity 'inactivating mutations' named entity 'CHIKV' named entity 'host-pathogen interface' named entity 'protease' named entity 'CHIKV' named entity 'protease' named entity 'CHIKV' named entity 'diphtheria toxin'

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