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

Brisse, Morgan; Ly, Hinh

The activated MAVS complex induces association of the inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) and the serine/threonine-protein kinase 1 (TBK1) (10-12), which collectively phosphorylate the interferon regulatory factors 3 and 7 (IRF3 and IRF7) (13) (Figure 1) . IKKε and TBK1 also interact with a number of other co-factors (152, 153) , such as the DEADbox helicase 3 (DDX3) (154) . The activated p-IRF3 (15) and p-IRF7 (14) then translocate into the nucleus and dimerize, where they then act as the primary transcription factors for IFNα and IFNβ, respectively. Existing evidence suggests that IFNα is more primarily produced in the earliest time points following RIG-I/MDA5 activation, while IFNβ is produced later and is responsible for more robust anti-viral control throughout the innate immune response period (155) . There is also a distinction between innate immune cell types for IFN1 production, as cells like fibroblasts and conventional dendritic cells produce IFNα and IFNβ (41, 156), while neutrophils only produce IFNβ (157) and plasmacytoid dendritic cells only produce IFNα primarily through the TLR signaling pathways (41, 158). Signaling through RIG-I is also known to be essential for the process of TLRmediated phagocytosis by macrophages (159) .