About: SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

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About: SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts Goto Sponge NotDistinct Permalink

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

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts
Creator	Lee, Benhur Jacques, David Chiu, Hsin-Ping Stevens, Christian Bhumkar, Akshay Freiberg, Alex Gambin, Yann Hunter, Dominic Moustaqil, Mehdi Ollivier, Emma Rudolffi-Soto, Paulina Sierecki, Emma Tol, Sarah
Source	BioRxiv
abstract	The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 and NSP5 on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 or NSP5, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type- I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients. Surprisingly, both NLRP12 and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 and should facilitate the search or development of more effective animal models for severe COVID-19. Finally, we discovered that one particular species of bats, David’s Myotis, possesses the five cleavage sites found in humans for NLRP12, TAB1 and IRF3. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.
has issue date	2020-06-05(xsd:dateTime)
bibo:doi	10.1101/2020.06.05.135699
has license	biorxiv
sha1sum (hex)	81e39fd18576e764884b71ea99a9092fd3262db0
schema:url	https://doi.org/10.1101/2020.06.05.135699
resource representing a document's title	SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts
schema:publication	bioRxiv
resource representing a document's body	covid:81e39fd18576e764884b71ea99a9092fd3262db0#body_text
is schema:about of	named entity 'genetically' named entity 'cleaved' named entity 'rapidly' named entity 'reservoir' named entity 'protease' named entity 'COVID-19' named entity 'presentation' named entity 'studies' named entity 'protease' named entity 'reservoir' named entity 'IRF3' covid:arg/81e39fd18576e764884b71ea99a9092fd3262db0 named entity 'Here' named entity 'proteins' named entity 'SARS-CoV' named entity 'cleavage' named entity 'motifs' named entity 'molecular' named entity 'possesses' named entity 'mediated' named entity 'absent' named entity 'human' named entity 'site' named entity 'TAB1' named entity 'cognate' named entity 'encoded' named entity 'IRF3' named entity 'protease' named entity 'cell-free system' named entity 'TAB1' named entity 'NSP3' named entity 'protease' named entity 'development' named entity 'based' named entity 'target' named entity 'comparative' named entity 'presentation' named entity 'endemic' named entity 'Hubei' named entity 'innate immune response' named entity 'NSP5' named entity 'NSP5' named entity 'cleavage site' named entity 'SARS2' named entity 'IRF3' named entity 'evolution' named entity 'COVID-19' named entity 'COVID-19' named entity 'China' named entity 'recombinant' named entity '3C-like protease' named entity 'protease' named entity 'TAB1' named entity 'TAB1' named entity 'proteases' named entity 'library' named entity 'murine' named entity 'NLRP12' named entity 'Hubei' named entity 'SARS-CoV-2 outbreak' named entity 'ACE2' named entity 'polyprotein' named entity 'viruses' named entity 'nucleocapsid' named entity 'virus' named entity 'Neovison vison' named entity 'ACE2' named entity 'SARS-CoV2' named entity 'type I interferon' named entity 'protein' named entity 'intermediate host' named entity 'NLRP12'

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