Antiviral innate immune response receptor RIG-I (also known as retinoic acid-inducible gene I protein RIG-1 or DExD/H-box helicase 58, DDX58) directly recognizes and binds to viral 5′-PPP RNA and short dsRNA through its helicase and repressor domain (Kato H et al. 2006). DDX58 activates downstream signaling cascade leading to the production of type I interferons (IFN) and proinflammatory cytokines. Type I IFN immune signaling has been found to be dampened upon infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and SARS-CoV-2 nucleocapsid (N) protein was shown to produce this effect (Li et al, 2020; Oh SJ & Shin OK 2021). SARS-CoV-2 N suppressed type I interferon (IFN) production in Sendai virus (SeV)-infected or poly(I:C)-stimulated human embryonic kidney 293T (HEK293T) cells by targeting the DDX58 signaling pathway (Chen K et al. 2020). Similar results were obtained using human alveolar basal epithelial (A549) cells. The viral N protein was found to bind DDX58 in HEK293T cells expressing Flag-DDX58 and pHA-N protein (Chen K et al. 2020). "Moreover, N protein was co-immunoprecipitated with endogenous RIG-I in Hela cells transfected with pHA-N, and the interaction was significantly enhanced upon SeV infection"- Chen K et al. 2020. The viral N protein interacts with the DExD/H domain of DDX58, which has ATPase activity (Chen K et al. 2020). RNA-dependent ATP hydrolysis by DDX58 (RIG-1) is thought to control the ability of DDX58 to discriminate non-self RNA from the cellular self RNA (Louber J et al. 2015; Dickey TH et al. 2019). These data suggest that SARS-CoV-2 N protein suppresses type I IFN production by targeting the ATP-dependent DDX58 signaling pathway (Chen K et al. 2020). In addition, N suppresses DDX58-mediated IFN-production via binding to RING-finger E3 ubiquitin ligase TRIM25 (Oh SJ & Shin OK 2021).