IL18RAP

IL18RAP (AcPL/CD218b) is an obligate co-receptor subunit of the IL-18 signaling receptor, functioning together with IL-18R1 to transduce cytokine signals into innate and adaptive immune responses (PMID:9792649). AcPL has no appreciable intrinsic IL-18 binding affinity, but its co-expression with IL-18R1 is non-redundantly required to activate NF-κB and JNK upon IL-18 stimulation, as a dominant-negative AcPL specifically abolishes this signaling (PMID:9792649). Beyond the canonical receptor, IL18RAP amplifies pattern-recognition-receptor signaling in human macrophages: it couples NOD2-initiated, caspase-1-dependent autocrine IL-18 to MAPK, NF-κB, PI3K, and calcium pathways, and restoring MAPK activation rescues the cytokine deficit of IL-18RAP-deficient macrophages (PMID:24842757). The magnitude of IL-18 (and IL-1β) responses tracks with IL-18RAP abundance, which is set by disease-associated regulatory variants and post-transcriptional control: the rs917997 genotype tunes cell-surface receptor levels and downstream signaling output (PMID:24842757, PMID:23891168), and the rs7559479 3′UTR allele modulates miR-136 binding to IL18RAP mRNA (PMID:29146643). Pharmacological targeting of IL18RAP is feasible: eupafolin binds IL-18RAP directly and disrupts receptor complex assembly, blocking IL-18-driven NF-κB and downstream IL-6/STAT3 signaling in cancer-associated fibroblasts (PMID:39265444).

1. 1998 High

   Established that IL-18 signaling requires a second receptor subunit beyond the ligand-binding chain, defining IL18RAP as an essential, non-redundant signal-transducing co-receptor.

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

   PMID:9792649

   Open questions at the time

   • Structural basis of the IL-18R1/IL18RAP/IL-18 ternary complex not resolved
   • Identity of the intracellular adaptors recruited to AcPL TIR domain not defined here
   • Does not address tissue-specific or quantitative regulation of the co-receptor
2. 2007 Low

   Asked whether IL18RAP output could be modulated by receptor isoform diversity, identifying truncated splice variants in testis as a candidate regulatory mechanism.

   Evidence RT-PCR amplification, cDNA sequencing, and computational protein modeling of human testicular tissue

   PMID:17897836

   Open questions at the time

   • No functional validation that truncated isoforms alter IL-18 signaling
   • Single method, single lab, no protein-level confirmation
   • Physiological role of testicular expression unexplored
3. 2013 Medium

   Connected a disease-risk SNP to IL18RAP function, showing that rs917997 genotype sets receptor expression and IL-18 responsiveness in immune cells.

   Evidence Flow cytometry of NK-cell surface IL-18RAP, T-cell gene expression, and IFNγ ELISA from genotype-stratified PBMCs

   PMID:23891168

   Open questions at the time

   • Correlative association, no direct demonstration that the SNP causally alters expression
   • Mechanism linking the variant to expression level not defined
   • Limited to specific immune cell types
4. 2014 High

   Defined IL18RAP as an amplifier of innate PRR signaling and showed quantitatively how a risk SNP lowers receptor surface levels to blunt cytokine responses.

   Evidence siRNA knockdown, pathway inhibitors, MAPK rescue constructs, flow cytometry, and cytokine ELISA in primary human macrophages

   PMID:24842757

   Open questions at the time

   • rs917997-to-expression mechanism (idx 2) is correlative across genotyped donors from a single lab
   • Direct interaction of IL18RAP with NOD2-pathway components not mapped
   • How a single co-receptor coordinately affects IL-18R1 and IL-1R1 surface levels unexplained
5. 2017 Medium

   Provided a post-transcriptional mechanism for IL18RAP dosage control, showing a 3′UTR allele alters miR-136 targeting.

   Evidence Luciferase reporter assay comparing rs7559479 allele variants in transfected cells

   PMID:29146643

   Open questions at the time

   • Single reporter assay with no endogenous mRNA or protein-level validation
   • Physiological contexts where miR-136 regulates IL18RAP not established
   • Effect on actual signaling output not measured
6. 2024 Medium

   Demonstrated that IL18RAP is pharmacologically druggable, with a direct binder disrupting receptor assembly and downstream tumor-supportive signaling.

   Evidence Biolayer interferometry, IP, NF-κB reporter/western, IL-6 ELISA, STAT3 phospho-assay, spheroid assays, and xenograft for eupafolin in cancer-associated fibroblasts

   PMID:39265444

   Open questions at the time

   • Eupafolin binding site and selectivity over IL-18R1 not mapped
   • Single-lab study without independent confirmation
   • In vivo target engagement vs off-target effects not separated

• The structural mechanism of receptor complex assembly and the precise intracellular signaling adaptors engaged by IL18RAP remain to be defined.
• No structural model of the IL-18R1/IL18RAP signaling complex in the corpus
• TIR-domain adaptor recruitment to AcPL not directly characterized
• In vivo / genetic knockout phenotype not represented