Activation of NLRP3 inflammasome by SARS-CoV-2 (WP4876)
Homo sapiens
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)
Authors
Alex Pico , Egon Willighagen , Marvin Martens , Eric Weitz , Martina Summer-Kutmon , and Nhung PhamActivity
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Cited In
- Target and drug predictions for SARS-CoV-2 infection in hepatocellular carcinoma patients (2022).
- Exploring the pharmacological mechanism of Duhuo Jisheng Decoction in treating intervertebral disc degeneration based on network pharmacology (2023).
- Identification of the Genetic Influence of SARS-CoV-2 Infections on IgA Nephropathy Based on Bioinformatics Method (2023).
- In silico transcriptional analysis of asymptomatic and severe COVID-19 patients reveals the susceptibility of severe patients to other comorbidities and non-viral pathological conditions (2023).
- Rare Variants in Inborn Errors of Immunity Genes Associated With Covid-19 Severity (2022).
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Organisms
Homo sapiensCommunities
COVID-19Annotations
Disease Ontology
severe acute respiratory syndrome viral infectious disease COVID-19Pathway Ontology
interleukin-1 signaling pathway regulatory pathway| Label | Type | Compact URI | Comment |
|---|---|---|---|
| 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 | |
| IL1B | GeneProduct | ensembl:ENSG00000125538 | |
| pro-IL1B | GeneProduct | ensembl:ENSG00000125538 | |
| ASC | GeneProduct | ensembl:ENSG00000103490 | |
| CASP1 | GeneProduct | ensembl:ENSG00000137752 | |
| pro-CASP1 | GeneProduct | ensembl:ENSG00000137752 | |
| orf3a | Protein | refseq:YP_009724391 |
References
- Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. Siu KL, Yuen KS, Castaño-Rodriguez C, Ye ZW, Yeung ML, Fung SY, et al. FASEB J. 2019 Aug;33(8):8865–77. PubMed Europe PMC Scholia