Activation of NLRP3 Inflammasome by SARS-CoV-2 (Homo sapiens)

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12IL1BCytokine StormNucleuschloroquineTRAF3NLRP3RELANFKB1NFKB1 p105UbOrf3aIL1Bpro-IL1Bpro-IL1BASCUbCASP1pro-CASP1


Description

Orf3a from SARS-CoV has been shown to bind TRAF3 and activate the NLRP3 inflammasome. The activation occurs at two points. First, by ubiquinating NF-kB (p105) to stimulate its proteolytic processing into mature NF-kB (p50), which can then go on to promote the transcription of pro-IL-1B together with RELA (p65). And second, by ubiquitinating ASC (PYCARD) in the NLRP3 inflammasome, which leads to its degradtion and the activation of caspase-1 (CASP1) that goes on to catalyze the production of mature IL-1B, leading to a cytokine storm. While Orf3a of SARS-CoV-2 only has 72.7% sequence identity with that of SARS-CoV, the TRAF3 binding motif PxQxS is 100% conserved (https://alexanderpico.github.io/SARS-CoV-2_Alignments/#Orf3a). Chloroquine, a multi-functional antiviral, decreases the production of IL-1B by affecting "the processing of primary transcripts in the nucleus, the transport of processed mRNA to the cytosol, and the degradation of mRNA." (Jang 2006)

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Ontology Terms

 

Bibliography

  1. Siu KL, Yuen KS, Castaño-Rodriguez C, Ye ZW, Yeung ML, Fung SY, Yuan S, Chan CP, Yuen KY, Enjuanes L, Jin DY; ''Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC.''; FASEB J, 2019 PubMed Europe PMC Scholia
  2. Jang CH, Choi JH, Byun MS, Jue DM; ''Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes.''; Rheumatology (Oxford), 2006 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
110321view22:52, 3 May 2020Marvin M2Changed the two unconnected lines into graphical lines
110211view13:12, 24 April 2020EgonwTyped proteins as Type="Protein"
109977view18:20, 8 April 2020AlexanderPicoupdated sars nodes per #covidpathways guidelines
109841view01:49, 2 April 2020AlexanderPicoupdated Orf3a with protein xref
109834view00:22, 2 April 2020AlexanderPicoModified description
109833view00:18, 2 April 2020AlexanderPicoAdded chloroquine and lit ref
109786view00:54, 1 April 2020AlexanderPicoModified description
109783view00:49, 1 April 2020AlexanderPicoOntology Term : 'regulatory pathway' added !
109782view00:49, 1 April 2020AlexanderPicoOntology Term : 'interleukin-1 signaling pathway' added !
109781view00:48, 1 April 2020AlexanderPicoOntology Term : 'severe acute respiratory syndrome' added !
109780view00:48, 1 April 2020AlexanderPicoOntology Term : 'viral infectious disease' added !
109779view00:37, 1 April 2020AlexanderPicoModified description
109778view00:34, 1 April 2020AlexanderPicoNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ASCGeneProductENSG00000103490 (Ensembl)
CASP1GeneProductENSG00000137752 (Ensembl)
IL1BGeneProductENSG00000125538 (Ensembl)
NFKB1 p105GeneProductENSG00000109320 (Ensembl)
NFKB1GeneProductENSG00000109320 (Ensembl)
NLRP3GeneProductENSG00000162711 (Ensembl)
Orf3aProteinYP_009724391 (RefSeq)
RELAGeneProductENSG00000173039 (Ensembl)
TRAF3GeneProductENSG00000131323 (Ensembl)
chloroquineMetaboliteQ422438 (Wikidata)
pro-CASP1GeneProductENSG00000137752 (Ensembl)
pro-IL1BRnaENSG00000125538 (Ensembl)

Annotated Interactions

No annotated interactions

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