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

Brisse, Morgan; Ly, Hinh

While RIG-I and MDA5 participate in the IFN1 signaling pathway (40), it is clear from animal modeling that they might be functionally distinct. While C57BL/6 MDA5 KO mice exhibit no obvious phenotypes (18), C57BL/6 RIG-I KO have high embryonic lethality as they don't live past 3 weeks of birth and experience growth retardation and liver degeneration (18, 41) . Furthermore, when RIG-I KO mice are back crossed onto the more genetically flexible 129S1 strain (18), these mice can spontaneously develop colitis symptoms (42). Clinical cases with mutations in RIG-I and MDA5 have distinct autoimmune presentations, with RIG-I mutations being associated with atypical Singleton-Merten Syndrome, while MDA5 mutations have been linked to classical Singleton-Merten Syndrome, Aicardi-Goutières syndrome, Systemic Lupus Erythematosus, Type 1 Diabetes and Graves disease (43, 44) (Figure 2 ). There is growing evidence that overt innate-immune interferon signaling plays a critical role in the development of other forms of autoimmune conditions (45). Taken together, this suggests that RIG-I and MDA5 may differ significantly in their roles during development as well as in responding to different types of viral infection that is partially dependent on the PAMPs that are available in any given context.