Previous studies on SARS-CoV revealed smart strategies to inhibit multiple steps in the NAS pathway and downstream signaling (Rose et al., 2010; Adedeji et al., 2013; Chan and Gack, 2016). As mentioned earlier, TRIM25 mediated ubiquitination activates RIG-I. Whereas, the N protein of SARS-CoV, which binds to TRIM25 and thereby prevents its association with RIG-I and hence activation. The ubiquitin usurped RIG-I is unable to mount the antiviral response, thereby disabling IFN-β production (Hu et al., 2017). N protein also antagonizes IFN signaling by directly interacting with IRF3, thereby inhibiting its phosphorylation and subsequent nuclear translocation (Kopecky-Bromberg et al., 2006; Kopecky-Bromberg et al., 2007). Similarly, M protein inhibits IRF3/IRF7 signaling by interfering with RIG-I, TBK1, IKKε, and TRAF3 activation complex formation (Siu et al., 2009). Acting at multiple pathways on host cells, Nsp1 inhibits IFN-β promoter activity and STAT1 phosphorylation which led to a decrease in the expression of various antiviral interferon-stimulated genes (ISGs; Wathelet et al., 2007). Chen et al. (2014) showed that papain-like protease (PLpro) directly associates with TRAF3, TBK1, IKKε, STING, and IRF3 and hence inhibits downstream IRF3/IRF7 signaling. In another study, Devaraj et al. (2007) showed that PLpro inhibits IRF3 phosphorylation and its subsequent nuclear translocation. ORF3b, ORF6, ORF8a, and ORF8b also play prominent roles in inhibiting IRF3 phosphorylation and its subsequent nuclear translocation (Kopecky-Bromberg et al., 2006; Freundt et al., 2010; Wong et al., 2018). ORF9b was shown to be associated with mitochondria and induced degradation of dynamin-related protein 1 (Drp1), thus altering mitochondrial function and sequestering MAVS into small puncta. Further, ORF9b was associated with recruitment of ubiquitin ligases PCBP2 and AIP4 E3 which led to ubiquitination of MAVS and eventually its degradation, as a result inhibiting IFN-β production (Shi et al., 2014). Thus, by associating with multiple proteins involved in NAS signaling, SARS-CoV antagonizes IFN signaling and synthesis of protective molecules like ISGs.