Vertebrate animals have developed innate and adaptive immune systems that defend them against microbial and other infections.1-3
The innate immune system is the first line of cellular defense against foreign invasion. When pathogens enter the cytoplasm, they are recognized by germline-encoded pattern-recognition receptors (PRRs) that initiate signaling events, resulting in the production of cytokines such as type I interferons (IFNs).2,3
IFNs have antiviral, antiproliferative, and immunomodulatory activities, and thus play crucial roles in host defense.4
The elucidation of mechanisms that link microbial invasion, engagement of PRRs, and activation of IFN responses has been an area of active investigation in recent years. The Toll-like receptor (TLR) family comprises a sub-group of highly conserved PRRs.5
Thus far, 10 isoforms (TLR1–TLR10) have been identified in humans, and mice are known to express an additional variant (TLR11). TLRs are roughly divided into two groups based on their subcellular localization. Cell surface-expressed TLRs (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11) recognize viral proteins and bacterial and fungal cell wall components. Other members of the family (TLR3, TLR7, TLR8, and TLR9) are expressed in intracellular compartments such as endosomes and sense mainly nucleic acids.5,6
Specifically, TLR3 senses double-stranded RNA (dsRNA) and TLR7 and TLR8 detect single-stranded RNA (ssRNA) of viral origin. However, TLR3-null cells respond to synthetic dsRNA, suggesting that additional mechanisms participate in the recognition of viral RNA.7
Two additional families have recently been characterized as members of the PRR superfamily: nucleotide-oligomerization domain (NOD)-like receptors (NLRs) and RIG-I (retinoic acid-inducible gene-I)-like receptors (RLRs). NLRs sense bacterial peptidoglycans in the cytoplasm, and RLRs detect viral nucleic acids in the cytosol.8
Three members of the RLR subfamily have been characterized thus far, including RIG-I, MDA5 (melanoma differentiation-associated gene 5), and LGP2 (laboratory of genetics and physiology 2). Each member senses specific viral RNA structures; the fact that RIG-I recognizes viruses that broadly impact human health, such as influenza and hepatitis C viruses, has sparked the interest of virologists and immunologists across the world.
This review is centered on structural and functional aspects of RIG-I. First, we discuss RNA features required for recognition by RLRs. Second, we provide current views regarding the role played by individual RIG-I domains in auto-repression, RNA binding, and signal transduction. Third, we present key studies that led to the elucidation of signaling events that follow RIG-I activation. Finally, we discuss viral- and host-mediated mechanisms that control the function and expression of RIG-I. Not surprisingly, deregulation of RIG-I-mediated events has been reported to contribute to the pathogenesis of human diseases, with an emphasis on autoimmune disorders. The final section of this review briefly discusses key work addressing this important issue.