About: Analysis of Coronavirus Temperature-Sensitive Mutants Reveals an Interplay between the Macrodomain and Papain-Like Protease Impacting Replication and Pathogenesis

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About: Analysis of Coronavirus Temperature-Sensitive Mutants Reveals an Interplay between the Macrodomain and Papain-Like Protease Impacting Replication and Pathogenesis Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Analysis of Coronavirus Temperature-Sensitive Mutants Reveals an Interplay between the Macrodomain and Papain-Like Protease Impacting Replication and Pathogenesis
Creator	Deng, Xufang Baker, Susan Mettelman, Robert O'brien, Amornrat O'brien, Timothy Pfeiffer, Julie Thompson, John
Source	Medline; PMC
abstract	Analysis of temperature-sensitive (ts) mutant viruses is a classic method allowing researchers to identify genetic loci involved in viral replication and pathogenesis. Here, we report genetic analysis of a ts strain of mouse hepatitis virus (MHV), tsNC11, focusing on the role of mutations in the macrodomain (MAC) and the papain-like protease 2 (PLP2) domain of nonstructural protein 3 (nsp3), a component of the viral replication complex. Using MHV reverse genetics, we generated a series of mutant viruses to define the contributions of macrodomain- and PLP2-specific mutations to the ts phenotype. Viral replication kinetics and efficiency-of-plating analysis performed at permissive and nonpermissive temperatures revealed that changes in the macrodomain alone were both necessary and sufficient for the ts phenotype. Interestingly, mutations in the PLP2 domain were not responsible for the temperature sensitivity but did reduce the frequency of reversion of macrodomain mutants. Coimmunoprecipitation studies are consistent with an interaction between the macrodomain and PLP2. Expression studies of the macrodomain-PLP2 portion of nsp3 indicate that the ts mutations enhance proteasome-mediated degradation of the protein. Furthermore, we found that during virus infection, the replicase proteins containing the MAC and PLP2 mutations were more rapidly degraded at the nonpermissive temperature than were the wild-type proteins. Importantly, we show that the macrodomain and PLP2 mutant viruses trigger production of type I interferon in vitro and are attenuated in mice, further highlighting the importance of the macrodomain-PLP2 interplay in viral pathogenesis. IMPORTANCE Coronaviruses (CoVs) are emerging human and veterinary pathogens with pandemic potential. Despite the established and predicted threat these viruses pose to human health, there are currently no approved countermeasures to control infections with these viruses in humans. Viral macrodomains, enzymes that remove posttranslational ADP-ribosylation of proteins, and viral multifunctional papain-like proteases, enzymes that cleave polyproteins and remove polyubiquitin chains via deubiquitinating activity, are two important virulence factors. Here, we reveal an unanticipated interplay between the macrodomain and the PLP2 domain that is important for replication and antagonizing the host innate immune response. Targeting the interaction of these enzymes may provide new therapeutic opportunities to treat CoV disease.
has issue date	2019-03-27(xsd:dateTime)
bibo:doi	10.1128/jvi.02140-18
bibo:pmid	30918076
has license	bronze-oa
sha1sum (hex)	2af60a6edf5657d366fc1f0ee1f3fda18b9418a3
schema:url	https://doi.org/10.1128/jvi.02140-18
resource representing a document's title	Analysis of Coronavirus Temperature-Sensitive Mutants Reveals an Interplay between the Macrodomain and Papain-Like Protease Impacting Replication and Pathogenesis
has PubMed Central identifier	PMC6613754
has PubMed identifier	30918076
schema:publication	Journal of Virology
resource representing a document's body	covid:2af60a6edf5657d366fc1f0ee1f3fda18b9418a3#body_text
is schema:about of	named entity 'proteases' named entity 'nsp3' named entity 'remove' named entity 'virulence factors' named entity 'Mutants' named entity 'POSE' named entity 'INVOLVED' named entity 'VIRAL PATHOGENESIS' named entity 'DISEASE' named entity 'Coimmunoprecipitation' named entity 'humans' named entity 'mutations' named entity 'control' named entity 'interplay' named entity 'MHV' named entity 'temperatures' named entity 'viruses' named entity 'Expression' named entity 'Analysis' named entity 'interplay' named entity 'host' named entity 'temperature' named entity 'virus' named entity 'emerging' named entity 'responsible' named entity 'complex' named entity 'studies' named entity 'mouse' named entity 'involved' named entity 'Protease' named entity 'Replication' named entity 'Viral' named entity 'nsp3' named entity 'ADP-ribosylation' named entity 'pathogenesis' named entity 'nsp3' named entity 'Coronaviruses' named entity 'PLP2' named entity 'papain' named entity 'PLP2' named entity 'viral replication' named entity 'viruses' named entity 'papain' named entity 'proteases' named entity 'Macrodomain' named entity 'Pathogenesis' named entity 'Papain' named entity 'GENE EXPRESSION' named entity 'Interplay' named entity 'Protease' named entity 'gene transcripts' named entity 'protein' named entity 'papain' named entity 'polyubiquitination' named entity 'vaccines' named entity 'nsp3' named entity 'phenotype' named entity 'enzymatic activity' named entity 'Murine coronavirus' named entity 'macrophages' named entity 'RNA' named entity 'polyprotein' named entity 'site-directed mutagenesis' named entity 'PCR' named entity 'mRNAs' named entity 'polyprotein' named entity 'nsp2' named entity 'weight loss' named entity 'PLP2' named entity 'PLpro' named entity 'MHV' named entity 'double-stranded RNA' named entity 'cycloheximide' named entity 'titer' named entity 'papain'

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