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) a0e 31034780 PubMed Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB J 2019 Siu KL Yuen KS Castaño-Rodriguez C Ye ZW Yeung ML Fung SY Yuan S Chan CP Yuen KY Enjuanes L Jin DY interleukin-1 signaling pathway PW:0000883 Pathway Ontology regulatory pathway PW:0000004 Pathway Ontology viral infectious disease DOID:934 Disease severe acute respiratory syndrome DOID:2945 Disease COVID-19 DOID:0080600 Disease