Induction of type I interferon by RNA viruses: cellular receptors and their substrates

Abstract

Virus recognition and induction of interferon (IFN) are critical components of the innate immune system. The Toll-like receptor (TLR) and RIG-I-like receptor families have been characterized as key players in RNA virus detection. Signaling cascades initiated by these receptors are crucial for establishment of an IFN signaling mediated antiviral state in infected and neighboring cells and containment of virus replication as well as initiation of the adaptive immune response. In this review, we focus on the diverse and overlapping functions of these receptors, their physiological importance, and respective viral inducers. We highlight the roles of TRL3, TLR7/8, retinoic acid inducible gene I, melanoma differentiation-associated gene 5, and the RNA molecules responsible for activating these viral sensors.

Fig. 1

Endosomal and cytoplasmic pathways for virus recognition and IFN production. In DCs, TLR7 and TLR8 located in endosomal compartments recognize viral ssRNA through either direct infection, autophagocytic uptake of viral material from cytoplasm or phagocytic uptake of other infected cells or vial particles. Both TLR 7 and 8 signal through adaptor MyD88, which through interaction with IRAK4/IRAK1/TRAF6 complex leads to phosphorylation and activation of IRF7 and subsequent IFN transcription. TLR3 located in endosomes of cDCs, macrophages, epithelial cells, and fibroblasts is activated by encountering dsRNA. Following its activation, TLR3 signals through its adaptor, TRIF which leads to activation of noncanonical IKK kinases (TBK1/IKKε) and subsequent phosphorylation and nuclear translocation of IRF3. NF-κB is also activated by TRIF mediated signaling through canonical IKK kinases (IKKα, β, and γ). Cytoplasmically located RIG-I and MDA5 are expressed in most cells and recognize 5′ppp containing dsRNA or long dsRNA, respectively. Both of these cytoplasmic sensors upon activation interact and signal through the mitochondrially located adaptor MAVS. This signaling pathway, analogous to that of TLR3, leads to activation of the canonical and noncanonical IKK kinases and the following nuclear transclocation of NF-κB and IRF3. Concurrent activation of IRF3 and NF-κB in turn allows for transcription of IFN genes and its synthesis and export

Fig. 2

RLR domains and their function. The RLR proteins can be divided into three basic domains. (1) The N-terminal CARD domain, composed of two tandem CARDs. (2) The central helicase domain, belonging to the DExD/H family of RNA helicases. (3) The unique C-terminal domain containing multiple regulatory functions (RD). The CARD domain, present in RIG-I and MDA5 but absent in LGP2, is required for interaction with MAVS and downstream signaling. CARD1 (C1) is involved in physical interaction with the CARD domain of MAVS, whereas CARD2 (C2) of RIG-I undergoes ubiquitination required for RIG-I activation. The helicase domain contains six conserved DExD/H helicase motifs and is involved in translocation/unwinding of RNA and ATP hydrolysis required for RLR function. The helicase domain is also implicated in RNA binding for all three RLR members. The RD is required for recognition and binding of RNA substrates. This domain provides specificity for either 5′ppp containing RNA (RIG-I) or dsRNA (MDA5, LGP2). RD is also required for homo- (RIG-I, MDA5) and hetero- (LGP2) dimer formation, necessary for signaling by these receptors. The RD of RIG-I additionally provides a unique function of autorepression, and RIG-I constructs lacking the RD domain constitutively induce IFN in the absence of RNA stimuli. *Activity has not been shown directly and is assumed based on sequence similarity to the helicase domain of RIG-I