IL1R9 Is Evolutionarily Related to IL18BP and May Function as an IL-18 Receptor

Abstract

The IL-1 families of ligands and receptors exhibit similarity of coding sequences, protein structures, and chromosomal positions, suggesting that they have arisen via duplication of ancestral genes. Within these families there is selectivity in ligand-receptor interactions as well as promiscuity. IL-18 and its receptor are members of these families. IL-18 is recognized as binding to the protein products of the IL18R1 and IL18RAP genes, and with high affinity to a separate IL-18 binding protein (IL-18BP). However, IL-18BP is anomalous, as it exhibits little resemblance to IL-18R proteins. Additionally, IL-18 is produced in the brain in medial habenula neurons, which project IL-18-containing axons to the interpeduncular nucleus. However, there is a lack of focal IL-18R expression in their terminal field. Given these anomalies, we hypothesized that another receptor for IL-18 may exist, and that IL18BP is evolutionarily related to this receptor. We examined Ensembl and National Center for Biotechnology Information databases to identify available IL18BP records (n = 86 species) and show through bioinformatics approaches that across mammalian species with IL18BP genes, IL-18BP is consistently most similar to IL-1R9 (IL-1R accessory protein-like 2), another member of the IL-1R family. IL-1R9 and the related IL-1R8, but not other IL-1R family members, exhibit an amino acid sequence similar to binding site A of human and viral IL-18BPs. Conserved intron/exon boundaries, protein structure, and key binding site amino acids suggest that IL18BP and IL1R9 are evolutionarily related, and that IL-1R9 and IL-1R8 may bind IL-18.

The family of the interleukin‐1 receptors

“…IL‐18BP is structurally very similar to the third domain (D3) of the IL‐1R5 and IL‐1R2 receptors, but there is no sequence homology and the encoding gene is different, although it seems that IL‐18BP and IL‐1R2 come from a common ancestral gene . Recently, the evolutionary relationship between IL‐18BP and the orphan receptor IL‐1R9 and IL‐1R10 has been also described, leading to the hypothesis that these receptors may actually act as alternative IL‐18 receptors in brain areas where IL‐18 is produced and active but IL‐1R5 is not expressed . Four isoforms of IL‐18BP have been described from alternative splicing of the human gene, which located on chromosome 11q13 (different from the location of the major IL‐1R gene cluster on chromosome 2q12, which includes the genes for IL‐1R2 and IL‐1R5), and called IL‐18BPa, b, c, and d .…”

“…Both IL-1R9 and IL-1R10 are evolutionarily related to IL-18BP. 104 Given that IL-18 is produced by brain neurons in areas where the classical IL-18-binding receptor IL-1R5 is not expressed, 282,283 it can be hypothesized that IL-1R9…”

“…384 Recently, the evolutionary relationship between IL-18BP and the orphan receptor IL-1R9 and IL-1R10 has been also described, leading to the hypothesis that these receptors may actually act as alternative IL-18 receptors in brain areas where IL-18 is produced and active but IL-1R5 is not expressed. 104 Four isoforms of IL-18BP have been described from alternative splicing of the human gene, which located on chromosome 11q13 (different from the location of the major IL-1R gene cluster on chromosome 2q12, which includes the genes for IL-1R2 and IL-1R5), and called IL-18BPa, b, c, and d. 220 Of these isoforms, only 2 (a and c) have a complete Ig domain and can bind IL-18, 220 while the biological function of the non-binding isoforms b and d is currently unknown.…”

“…While the IL‐18‐inhibitory capacity of IL‐18BP is widely acknowledged, there are suggestions of additional distinct activities, e.g. as an alternative receptor for IL‐18 in the brain and as a transporter of IL‐18 to maintain physiological rates of NK cell maturation …”

Redefining the ancestral origins of the interleukin-1 superfamily

“…The interleukin-1 (IL-1) family of cytokines and corresponding receptors constitute one of the main signalling components of inflammation 1 , 2 . It is commonly reported that there are 11 members of the IL-1 ligand family 1 – 3 and 10 members of the IL-1 receptor family 4 , 5 . The concepts of protein and gene families originally arose from evolutionary analysis where individuals are grouped into families based on shared common ancestry 6 – 8 .…”