Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

Brisse, Morgan; Ly, Hinh

There is also increasing evidence that RIG-I and MDA5 have additional distinct molecular functionalities in immune signaling (43). It is well-established that the interferon regulatory factor (IRF) and innate immune NFκB cytokine signaling pathways have many areas of cross-regulation and expression (46). Accordingly, both RIG-I and MDA5 have been shown to activate NFκB signaling during RSV infection, but only RIG-I appears to act upstream of the canonical IκBα-NFκB pathway (47, 48) (Figure 1) . While both are known to activate NFκB mediated expression of IL-6 and pro-IL-1β through the interaction of CARD9 with BCL10 (49, 50), the independence of MDA5 from the IκBα pathway suggests that it influences NFκB signaling in other as yet uncharacterized ways (43). A possible explanation for MDA5's independence from the IκBα pathway may be that MDA5-mediated NFκB (but not IRF) signaling requires TRIM25, which activates RIG-I by ubiquitination (to be discussed in detail below). This potentially implicates TRIM25 in other mechanisms besides activating RIG-I (51, 52). RIG-I (but not MDA5) also induces inflammasome assembly-mediated cleavage and maturation of pro-IL-1β by caspase 1 (24, 34, 53) . Finally, RIG-I has been shown to inhibit RNAi complexes mediated by the endoribonuclease Dicer, which is encoded by the DICER1 gene and cleaves dsRNA and pre-micro RNA into short single-stranded RNA fragments known as small interfering RNA (siRNA) and microRNA FIGURE 1 | RIG-I/MDA5 signaling pathway RIG-I and MDA5 are first activated by recognition of PAMP dsRNA, which causes them to interact with MAVS. Following the activation of MAVS by RIG-I/MDA5, a molecular cascade involves the interaction of IKKε and TBK1, which is followed by phosphorylation of the transcription factors IRF3 and IRF7, ensure to translocate the phosphorylated p-IRF3 and p-IRF7 into the nucleus, where they dimerize and bind to transcription factor binding sites of the IFNα and IFNβ genes to activate their transcriptions. Expression and exportation of these genes into the cellular milieu trigger the IFN1 signaling cascade in an autocrine or paracrine fashion to induce expression of hundreds of interferon stimulated genes (ISGs) and inflammatory genes to confer antiviral resistance. RIG-I and MDA5 also activate the NF-κB pathway. RIG-I appears to act upstream of the canonical pathway, which results in the translocation of the two functional NF-κB units (p50 and p65) into the nucleus, while MDA5 appears to affect NF-κB expression independently from this pathway. Figure created using BioRender software.