Figure 1. Overview of RLRs signaling pathway. Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) recognize the genomic RNA or RNA replication intermediates of viruses as cytoplasmic RNA sensors. Following viral infection, melanoma differentiation-associated protein 5 (MDA5) recognizes cytoplasmic viral long-scale double-stranded RNA (dsRNA) whereas RIG-I recognizes short viral dsRNA (non-self RNA). Upon recognition of viral dsRNA, MDA5 and RIG-I specifically ubiquitinated by TRIM65 and TRIM25 respectively initiate antiviral innate immune response via specific interaction with mitochondrial antiviral signaling protein (MAVS) by CARD-CARD interaction. MAVS modulates nuclear factor-kB (NF-kB) activity via IKK complex (IKK α/β/γ) activation. MAVS also interacts with TRAFs translocated onto mitochondria upon viral infection and subsequently induces recruitment of TBK1 and IκB kinase-ɛ (IKKɛ) to promote phosphorylation of interferon (IFN) regulatory factor 3 (IRF3) and IRF7. Phosphorylated IRF3 and IRF7 cause their homo-dimerization which is translocated to the nucleus. In the nucleus, homo-dimerized IRF3 and IRF7 bind to specific binding sites in the IFNβ and IFNα promoter respectively to stimulate type I IFN synthesis. Secreted type I IFNs (IFNβ and IFNα) binds to interferon alpha and beta receptor subunit 1 (IFNAR1) and subsequently induces phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2, leading to the induction of nuclear translocation of IRF7/STAT1/STAT2 complex followed by promotion of IFN-stimulated genes (ISGs) transcription. Solid arrows indicate direct signaling. Dashed arrows indicate indirect signaling.