IL18RAP

IL18RAP is an obligate accessory subunit of the IL-18 receptor complex that does not bind IL-18 directly but heterodimerizes with IL18R1 to form a signaling-competent receptor, activating NF-κB, JNK, MAPK, PI3K, and calcium pathways downstream of IL-18 (PMID:9792649, PMID:24842757). In macrophages, IL18RAP amplifies pattern-recognition receptor (PRR)-induced cytokine secretion by transducing autocrine IL-18 signals generated through NOD2/caspase-1, and its loss impairs MAPK activation and downstream cytokine production (PMID:24842757). IL18RAP expression is modulated post-transcriptionally by miR-136 binding at a 3′-region SNP and by alternative splicing that generates truncated isoforms (PMID:29146643, PMID:17897836). Disease-associated variants (rs917997) reduce IL18RAP surface expression on NK cells and T cells, altering IL-18 responsiveness and IFN-γ output (PMID:23891168, PMID:24842757).

1. 1998 High

   Established that IL18RAP is not a direct IL-18 binder but an essential co-receptor that heterodimerizes with IL18R1 to activate NF-κB and JNK, resolving the composition of the functional IL-18 receptor complex.

   Evidence Transient transfection NF-κB reporter assays, JNK activation assays, dominant-negative overexpression, and in vitro binding assays

   PMID:9792649

   Open questions at the time

   • Structural basis of IL18RAP–IL18R1 heterodimerization not determined
   • Downstream signaling beyond NF-κB and JNK not mapped
   • In vivo requirement not tested
2. 2007 Medium

   Revealed that IL18RAP mRNA undergoes alternative splicing yielding truncated isoforms, raising the possibility of endogenous regulation of IL-18 signaling at the receptor level.

   Evidence RT-PCR and cDNA sequencing of human testicular and other tissues with computational modeling of isoforms

   PMID:17897836

   Open questions at the time

   • No functional assay of truncated isoforms was performed
   • Protein-level expression of truncated variants not confirmed
   • Tissue-specific ratios of splice forms and their physiological impact unknown
3. 2013 Medium

   Linked the rs917997 genotype to differential IL18RAP surface expression on NK cells and T cells and to altered IL-18/IL-12-driven IFN-γ production, connecting a GWAS-identified variant to a discrete receptor-level mechanism.

   Evidence Flow cytometry on NK cells, gene expression in activated T cells, IFN-γ ELISA from PBMCs

   PMID:23891168

   Open questions at the time

   • Single-lab study; independent replication in larger cohorts not shown
   • Molecular mechanism by which the SNP alters surface expression not defined
   • Cell-type specificity of the effect beyond NK and T cells not explored
4. 2014 High

   Demonstrated that IL18RAP amplifies innate immune PRR responses by transducing autocrine IL-18 generated via NOD2/caspase-1, broadening IL18RAP's role from simple co-receptor to an amplifier of MAPK, NF-κB, PI3K, and calcium signaling in macrophages.

   Evidence siRNA knockdown in primary human monocyte-derived macrophages, signaling pathway analysis, MAPK reconstitution rescue, flow cytometry for surface protein

   PMID:24842757

   Open questions at the time

   • Relative contributions of each downstream pathway (PI3K, calcium, MAPK) to cytokine output not dissected
   • Whether IL18RAP amplifies signals from PRRs other than NOD2 not tested
   • In vivo validation of autocrine loop not performed
5. 2017 Medium

   Identified a post-transcriptional regulatory mechanism whereby the rs7559479 A allele enhances miR-136 binding to IL18RAP mRNA, explaining allele-specific modulation of IL-18 system activity.

   Evidence Luciferase reporter assays with allele-specific constructs

   PMID:29146643

   Open questions at the time

   • Effect on endogenous IL18RAP protein levels not measured
   • Physiological relevance of miR-136 regulation in immune cells not demonstrated
   • Whether other miRNAs co-regulate IL18RAP not explored
6. 2024 Medium

   Confirmed IL18RAP's requirement for receptor complex formation by showing that eupafolin directly binds IL18RAP, blocks IL18R complex assembly, inhibits NF-κB activation, and reduces IL-6/STAT3 signaling in cancer-associated fibroblasts and gastric cancer cells.

   Evidence Biolayer interferometry, molecular docking, immunoprecipitation, lentiviral knockdown, in vitro and in vivo tumor models

   PMID:39265444

   Open questions at the time

   • Eupafolin binding site on IL18RAP and selectivity over related IL-1 family receptors not structurally resolved
   • Single study; independent confirmation of the eupafolin–IL18RAP interaction needed
   • Whether IL18RAP targeting in the tumor microenvironment is therapeutically viable remains untested in clinical settings

• No high-resolution structure of the IL18RAP–IL18R1–IL-18 ternary complex exists, and the precise molecular basis for how IL18RAP enhances IL-18 binding affinity and initiates TIR-domain signaling remains undefined.
• No cryo-EM or crystal structure of the heterotrimeric complex
• TIR-domain signaling initiation mechanism upon heterodimerization not dissected
• In vivo conditional knockout phenotype not reported