Sensing of viral RNAs activates signaling by RIG-I and MDA-5 that leads to type I interferon production appropriate for defense against viral infection (Fig. 3.21). Before infection by viruses, RIG-I and MDA-5 are in the cytoplasm in an autoinhibited configuration that is stabilized by interactions between the CARD and helicase domains. These interactions are disrupted upon infection when viral RNA associates with the helicase domains of RIG-I or MDA-5, freeing the two CARD domains for other interactions. The more amino-proximal portion of the two CARD domains can then recruit E3 ligases, including TRIM25 and Riplet (encoded by RNF153), which initiate K63-linked polyubiquitin scaffolds (see Section 3-7), either as free polyubiquitin chains or on linkages within the second CARD domain. Precise details are unclear, but this scaffold appears to help RIG-I and MDA-5 interact with a downstream adaptor protein called MAVS (mitochondrial antiviral signaling protein). MAVS is attached to the outer mitochondrial membrane and contains a CARD domain that may bind RIG-I and MDA-5. This aggregation of CARD domains, as in the inflammasome, may initiate aggregation of MAVS. In this state, MAVS propagates signals by recruiting various TRAF family E3 ubiquitin ligases, including TRAF2, TRAF3, TRAF5, and TRAF6. The relative importance of each E3 ligase may differ between cell types, but their further production of K63linked polyubiquitin leads to activation of TBK1 and IRF3 and production of type I interferons, as described for TLR-3 signaling (see Fig. 3.16), and also to activation of NFκB. Some viruses have evolved countermeasures to thwart the protection conferred by RLRs. For example, even though the negative-sense RNA genome of influenza virus replicates in the nucleus, some viral RNA transcripts produced during influenza infection are not capped but must be translated in the cytoplasm. The influenza A nonstructural protein 1(NS1) inhibits the activity of TRIM25, and thereby interrupts the antiviral actions that RIG-I might exert against infection.
3-11 Cytosolic DNA sensors signal through STING to induce production of type I interferons.
Innate sensors that recognize cytoplasmic RNA use specific modifications, such as the 5ʹ cap, to discriminate between host and viral origin. Host DNA is generally restricted to the nucleus, but viral, microbial, or protozoan DNA may become located in the cytoplasm during various stages of infection. Several innate sensors of cytoplasmic DNA have been identified that can lead to the production of type I interferon in response to infections. One component of the DNA-sensing pathway, STING (stimulator of interferon genes), was identified in a functional screen for proteins that can induce expression of type I interferons. STING (encoded by TMEM173) is anchored to the endoplasmic reticulum membrane by an amino-terminal tetraspan transmembrane domain; its carboxy-terminal domain extends into the cytoplasm and interacts to form an inactive STING homodimer.