</head> <body>Authors: <br/> Sara Sadat Aghamiri, Computational Systems Biology Engineer; Institut national de la santé et de la recherche médicale- INSERM; Laboratoire de recherche européen pour la polyarthrite rhumatoïde-GenHotel <br/> <br/> Vidisha Singh, GenHotel Laboratory, University of Evry-Paris Saclay, Évry, France <br/> <br/> Anna Niarakis, University of Évry Val d'Essonne, Évry, France <br/> <br/> Description from Fung and Liu, 2019: Mild HCoVs such as HCoV-229E typically induce a high level of IFN-I production. SARS-CoV and MERS-CoV were shown to utilize mechanisms to suppress the activation of host innate immune response. Several structural proteins (M and N), nonstructural proteins (nsp1 and nsp3), and accessory proteins of SARS-CoV and/or MERS-CoV were identified as interferon antagonists. Innate immunity plays critical for the initial detection and restriction of pathogens and activation of the adaptive immune response. Effective activation of innate immunity relies on the: Recognition pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) PRRs recruit adaptor proteins, which initiate complicated signaling pathways involving multiple kinases. Activation of crucial transcription factors including interferon regulatory factor 3 (IRF3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and AP-1. These factors promote the production of type I interferons (IFN-I), which are released and act on neighboring cells by binding to IFN-α/β receptor (IFNAR) The antiviral activity of IFN-I is mediated by the induction of numerous interferon-stimulated genes (ISGs), which antagonize viral replication by various mechanisms. </body> </html> </notes> <annotation> <celldesigner:extension> <celldesigner:modelVersion>4.0</celldesigner:modelVersion> <celldesigner:modelDisplay sizeX="8010" sizeY="4906"/> <celldesigner:listOfIncludedSpecies> <celldesigner:species id="s2513" name="Orf8b"> <celldesigner:notes> <html xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body> Human sars cov Protein non-structural 8b </body> </html> </celldesigner:notes> <celldesigner:annotation> <celldesigner:complexSpecies>s2558</celldesigner:complexSpecies> <celldesigner:speciesIdentity> <celldesigner:class>PROTEIN</celldesigner:class> <celldesigner:proteinReference>pr808</celldesigner:proteinReference> 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<head> <title/> </head> <body>SIGNOR-SCISOVG </body> </html> </notes> <annotation> <celldesigner:extension> <celldesigner:positionToCompartment>inside</celldesigner:positionToCompartment> <celldesigner:speciesIdentity> <celldesigner:class>PHENOTYPE</celldesigner:class> <celldesigner:name>Proinflammatory cytokine expression_Inflammation</celldesigner:name> </celldesigner:speciesIdentity> </celldesigner:extension> <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/"> <rdf:Description rdf:about="#s2518"> <bqbiol:isEncodedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:mesh:D007249"/> </rdf:Bag> </bqbiol:isEncodedBy> </rdf:Description> </rdf:RDF> </annotation> </species> <species metaid="s2604" id="s2604" name="type I IFN response" 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initialAmount="0"> <annotation> <celldesigner:extension> <celldesigner:positionToCompartment>inside</celldesigner:positionToCompartment> <celldesigner:speciesIdentity> <celldesigner:class>PROTEIN</celldesigner:class> <celldesigner:proteinReference>pr833</celldesigner:proteinReference> </celldesigner:speciesIdentity> </celldesigner:extension> </annotation> </species> <species metaid="s2611" id="s2611" name="IKKa" compartment="c2" initialAmount="0"> <annotation> <celldesigner:extension> <celldesigner:positionToCompartment>inside</celldesigner:positionToCompartment> <celldesigner:speciesIdentity> <celldesigner:class>PROTEIN</celldesigner:class> <celldesigner:proteinReference>pr834</celldesigner:proteinReference> </celldesigner:speciesIdentity> </celldesigner:extension> </annotation> </species> <species metaid="s2612" id="s2612" name="IKKb" compartment="c2" initialAmount="0"> <annotation> <celldesigner:extension> 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</celldesigner:listOfModifications> </celldesigner:state> </celldesigner:speciesIdentity> </celldesigner:extension> </annotation> </species> <species metaid="s2528" id="s2528" name="IRF3" compartment="c2" initialAmount="0"> <annotation> <celldesigner:extension> <celldesigner:positionToCompartment>inside</celldesigner:positionToCompartment> <celldesigner:speciesIdentity> <celldesigner:class>PROTEIN</celldesigner:class> <celldesigner:proteinReference>pr29</celldesigner:proteinReference> <celldesigner:state> <celldesigner:listOfModifications> <celldesigner:modification residue="rs2" state="phosphorylated"/> </celldesigner:listOfModifications> <celldesigner:listOfStructuralStates> <celldesigner:structuralState structuralState="active"/> </celldesigner:listOfStructuralStates> </celldesigner:state> </celldesigner:speciesIdentity> </celldesigner:extension> </annotation> </species> <species metaid="s2569" id="s2569" name="IRF7" compartment="c2" initialAmount="0"> <annotation> 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</celldesigner:speciesIdentity> <celldesigner:listOfCatalyzedReactions> <celldesigner:catalyzed reaction="re10"/> <celldesigner:catalyzed reaction="re13"/> </celldesigner:listOfCatalyzedReactions> </celldesigner:extension> </annotation> </species> <species metaid="s2647" id="s2647" name="IRF3_homodimer" compartment="c2" initialAmount="0"> <annotation> <celldesigner:extension> <celldesigner:positionToCompartment>inside</celldesigner:positionToCompartment> <celldesigner:speciesIdentity> <celldesigner:class>COMPLEX</celldesigner:class> <celldesigner:name>IRF3_homodimer</celldesigner:name> </celldesigner:speciesIdentity> </celldesigner:extension> </annotation> </species> <species metaid="s2649" id="s2649" name="IRF3_homodimer" compartment="c3" initialAmount="0"> <annotation> <celldesigner:extension> <celldesigner:positionToCompartment>inside</celldesigner:positionToCompartment> <celldesigner:speciesIdentity> <celldesigner:class>COMPLEX</celldesigner:class> 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id="re69" reversible="false"> <notes> <html xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body>SIGNOR-SCISOVG: SIGNOR-260587 </body> </html> </notes> <annotation> <celldesigner:extension> <celldesigner:reactionType>STATE_TRANSITION</celldesigner:reactionType> <celldesigner:baseReactants> <celldesigner:baseReactant species="s2576" alias="sa187"> <celldesigner:linkAnchor position="S"/> </celldesigner:baseReactant> </celldesigner:baseReactants> <celldesigner:baseProducts> <celldesigner:baseProduct species="s2576" alias="sa186"> <celldesigner:linkAnchor position="NNW"/> </celldesigner:baseProduct> </celldesigner:baseProducts> <celldesigner:connectScheme connectPolicy="direct" rectangleIndex="0"> <celldesigner:listOfLineDirection> <celldesigner:lineDirection index="0" value="unknown"/> </celldesigner:listOfLineDirection> </celldesigner:connectScheme> <celldesigner:line width="1.0" color="ff000000"/> <celldesigner:listOfModification> <celldesigner:modification type="TRIGGER" 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xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body>WP4868: The inhibition of SARS-CoV-2 PLpro by GRL0617 is proposed based on Ratia, et al. 2008 and 100% sequence identity between SARS-CoV and SARS-CoV-2 across all 13 residues of PLpro involved in binding GRL0617 (82.9% identity across 316 amino acids) as determined by the alignment of RefSeq YP_009725299.1 and PDB 3E9S (https://alexanderpico.github.io/SARS-CoV-2_Alignments/#Nsp3_PLpro_domain). 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