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

Brisse, Morgan; Ly, Hinh

The innate immune response is a combination of non-specific defense mechanisms by the host that are critical for early detection and inhibition of pathogen growth before the adaptive immune response has time to produce proper cell-mediated immunity, such as the development of antibodies and cytotoxic T-lymphocyte responses (CTL) against the invading pathogen and/or the pathogen-infected cells (5) . Cells of the innate immune arm, such as leukocytes and epithelial cells, are able recognize general components of the microbes (e.g., viruses) that are shared among related microbes. These microbial structures are called pathogen-associated molecular patterns (PAMPs) (e.g., viral dsRNA) that are specifically recognized by the cellular pattern recognition receptors (PRRs) (e.g., RIG-I, MDA5, or Tolllike receptors TLRs) which are then activated (Figure 1) . The specific signaling mechanisms of RIG-I and MDA5 activation will be discussed in detail below. Here, the cascade of event leading to IFN1 production is briefly summarized. Upon binding to PAMP (e.g., dsRNA), the activated RIG-I and MDA5 interact with the mitochondrial antiviral signaling proteins (MAVS), which forms a multilayered protein complex contain several different proteins (6) (7) (8) (9) . The MAVS complex then catalyzes the interaction of inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) and the serine/threonine-protein kinase 1 (TBK1) (10) (11) (12) , which phosphorylate the transcription factors interferon regulatory factors 3 and 7 (IRF3 and IRF7) (13). Phosphorylated p-IRF7 (14) and -pIRF3 (15) factors then dimerize and translocate into the nucleus, where they activate the expression of the type 1 interferon genes (IFN1: IFNα and IFNβ). IFN1 proteins are then exported out of the cell to activate IFN1 signaling cascade by binding to their receptor (the IFNα/β receptor or IFNAR) either on the same cells or neighboring cells in an autocrine or paracrine fashion. This results in the production of more IFN1 (in a positive feedback loop) and a variety of interferon-stimulated genes (ISGs), which mediate vasodilation near the site of the pathogen infection and uptake of fluid, recruitment of innate immune cells, such as macrophages, neutrophils, and dendritic cells to the site of the infection that is aided by chemokine gradients to mediate innate immune cell-mediated killing of the infected cells (16).