SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes

Shi, Chong-Shan; Nabar, Neel R.; Huang, Ning-Na; Kehrl, John H.

The SARS-CoV is an enveloped, positive-strand RNA virus that encodes a set of accessory proteins, several of which target the innate immune response. Open reading frame (ORF) 8a and ORF9b trigger cellular apoptosis; ORF7a activates nuclear factor-κB (NF-κB); ORF3b upregulates the expression of several cytokines and chemokines; ORF6 limits interferon production; ORF3a induces necrotic cell death; and ORF8b induces cellular DNA synthesis and suppresses the expression of the viral envelope protein 10, 11 . Recently, we found that ORF9b localizes to mitochondrial membranes and reduces mitochondrial-associated adapter molecule MAVS, severely limiting the interferon response 12 . Of note, ORF8b is of interest as ORF8 encoded a single polypeptide during the early phase of the SARS epidemic, while in the later stages a 29-nucleotide deletion split it into two ORFs, ORF8a and ORF8b. They encode 39-and 84-residue polypeptides respectively. The splitting of ORF8 is thought to confer evolutionary advantage to the virus, and accordingly virus expressing ORF8b is better able to replicate in the presence of interferon 10, 13 .