Activation of NLRP3 inflammasome by SARS-CoV-2 (WP4876)

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)
last edited

Authors

AlexanderPico, Egonw, Marvin M2, and Eweitz

Cited In

Organism

Homo sapiens

Communities

COVID-19

Annotations

Disease Ontology: viral infectious disease COVID-19 severe acute respiratory syndrome

Pathway Ontology: interleukin-1 signaling pathway regulatory pathway

Participants

Label Type Compact Identifier
Chloroquine Metabolite wikidata:Q422438
TRAF3 GeneProduct ensembl:ENSG00000131323
NLRP3 GeneProduct ensembl:ENSG00000162711
RELA GeneProduct ensembl:ENSG00000173039
NFKB1 GeneProduct ensembl:ENSG00000109320
NFKB1 p105 GeneProduct ensembl:ENSG00000109320
Orf3a Protein refseq:YP_009724391
IL1B GeneProduct ensembl:ENSG00000125538
pro-IL1B GeneProduct ensembl:ENSG00000125538
pro-IL1B Rna ensembl:ENSG00000125538
ASC GeneProduct ensembl:ENSG00000103490
CASP1 GeneProduct ensembl:ENSG00000137752
pro-CASP1 GeneProduct ensembl:ENSG00000137752

References

  1. Jang C-H, Choi J-H, Byun M-S, Jue D-M. Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. Rheumatology (Oxford). 2006 Jun;45(6):703–10. PubMed Europe PMC Scholia
  2. Siu K-L, Yuen K-S, Castaño-Rodriguez C, Ye Z-W, Yeung M-L, Fung S-Y, et al. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB J. 2019 Aug;33(8):8865–77. PubMed Europe PMC Scholia