Innate immune RNA-sensing receptors (RNA-sensing PRRs)

Innate immune RNA-sensing receptors are a specialized group of pattern recognition receptors (PRRs) responsible for detecting foreign or mislocalized ribonucleic acids, primarily from viruses and bacteria. This group includes endosomal Toll-like receptors, such as TLR3, TLR7, and TLR8, as well as cytosolic RIG-I-like receptors, including RIG-I (DDX58) and MDA5 (IFIH1) [1, 2]. These receptors recognize distinct RNA structures, such as double-stranded RNA or 5-prime-triphosphorylated RNA, which are characteristic of viral replication intermediates [2, 3]. Upon activation, these sensors trigger signaling cascades through adapter proteins like MAVS or TRIF, leading to the activation of transcription factors IRF3/7 and NF-kappaB [3]. This process results in the robust production of Type I interferons and pro-inflammatory cytokines, which are essential for establishing an antiviral state [4]. In disease contexts, dysregulation or chronic activation of these receptors by endogenous RNA can lead to autoimmune conditions such as systemic lupus erythematosus or Aicardi-Goutieres syndrome [4, 5]. From a therapeutic perspective, agonists of these receptors are being developed as potent vaccine adjuvants and cancer immunotherapies to stimulate the innate immune system against tumors [5]. Conversely, antagonists are being investigated to treat autoinflammatory diseases by dampening excessive nucleic acid-driven signaling [1, 5].

Other names

RNA-sensing pattern recognition receptorsNucleic acid-sensing receptorsEndosomal and cytosolic RNA sensorsTLR3/7/8 and RIG-I-like receptors

Agonists bind to conserved structural motifs in non-self RNA, inducing receptor oligomerization and recruitment of signaling adapters such as MAVS, TRIF, or MyD88 to activate interferon regulatory factors (IRFs) and NF-kappaB, ultimately driving the expression of antiviral and inflammatory genes [1, 2, 3].