Retinoic acid-inducible gene I-like receptor (RLR) pathway (RLR)

The Retinoic acid-inducible gene I-like receptor (RLR) pathway is a fundamental component of the innate immune system that detects the presence of viral RNA in the cytosol [1]. It consists of three primary members: RIG-I (DDX58), MDA5 (IFIH1), and LGP2 (DHX58), which are DExD/H-box RNA helicases that function as pattern recognition receptors (PRRs) [2, 3]. Upon recognizing specific molecular patterns, such as 5-triphosphorylated or long double-stranded RNA, these receptors undergo a conformational change and aggregate with the Mitochondrial Antiviral-Signaling protein (MAVS) [1, 3]. This assembly initiates a signaling cascade involving TBK1 and IKK kinases, ultimately activating the transcription factors IRF3, IRF7, and NF-kappaB [3]. The activation leads to the robust production of Type I and Type III interferons and other pro-inflammatory cytokines that establish an antiviral state [1]. In clinical applications, the RLR pathway is targeted by synthetic agonists to enhance antiviral defenses or to stimulate the immune system against cold tumors in oncology [4]. However, excessive or chronic activation of this pathway is associated with interferonopathies and autoimmune conditions like systemic lupus erythematosus and Aicardi-Goutieres syndrome [1, 3].

Other names

RLR pathwayRIG-I-like helicasesRIG-I-like receptorsCytosolic RNA sensing pathwayDDX58/IFIH1/DHX58 signaling

RLR agonists bind to the helicase or C-terminal domains of RIG-I or MDA5, inducing a conformational change that allows interaction with MAVS, leading to the activation of IRF3/7 and NF-kappaB and subsequent production of Type I interferons [1, 3].