Many viral infections, especially those of RNA viruses, result in the delivery and replication of viral RNA in the cytosol of infected host cells. These viral RNAs often contain 5’-triphosphate (5’-ppp) and panhandle-like secondary structures composed of double-stranded segments. These features are recognized by members of the RIG-I-like Receptor (RLR) family, which includes RIG-I, MDA5, and LGP2 (Fujita, 2009
; Yoneyama et al., 2004
). All RLRs contain a DEAD/H-box RNA helicase domain in the middle. In addition, RIG-I and LGP2 contain a C-terminal regulatory domain (RD) that binds to 5’-pppRNA. MDA5, on the other hand, recognizes long double-stranded RNAs (dsRNAs) as well as single-stranded RNAs (ssRNAs) derived from picornaviruses. RIG-I and MDA5, but not LGP2, also contain two N-terminal CARD domains that interact with the CARD domain of the adaptor protein MAVS (also known as IPS-1, VISA or CARDIF), which resides in the mitochondrial outer membrane. MAVS interacts with STING (also known as MITA), a transmembrane protein in mitochondria and the endoplasmic reticulum (ER). On the ER membrane, STING associates with the TRAP complex, which may be involved in recruiting the protein kinases TBK1 and IKKε to phosphorylate the transcription factor IRF3. MAVS also recruits the ubiquitin ligases TRAF3 and TRAF6, which activate TBK1 and another kinase IKK, respectively. IKK phosphorylates IκB, an inhibitor of the master transcription factor NF-κB, leading to the ubiquitination of IκB and its subsequent degradation. NF-κB then enters the nucleus to turn on a plethora of proinflammatory genes. NF-κB also associates with IRF3, IRF7 and other transcription factors to induce production of IFN-β.
Infection by some DNA viruses and intracellular bacteria also leads to potent induction of type-1 interferons. The cytosolic DNAs introduced by these pathogens are detected by distinct sensors. AT-rich DNA is recognized by RNA polymerase III, which transcribes the DNA into 5’-pppRNA that triggers the RIG-I pathway. Cytosolic DNA can also induce interferons through RIG-I-independent mechanisms, including those involving other DNA sensors such as DAI and adaptor proteins such as STING. In addition to inducing production of type 1 interferons, cytosolic DNA can activate the inflammasome, which converts the IL-1β precursor protein into the mature cytokine. In this pathway, cytosolic DNA is recognized by AIM2, which forms a complex with ASC and procaspase-1, resulting in caspase-1 activation (Schroder et al., 2009
). Cytosolic RNA can also activate the inflammasome through RIG-I, which engages ASC to activate caspase-1.