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IL1R9 Is Evolutionarily Related to IL18BP and May Function As an IL-18 Receptor Chris S

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IL1R9 Is Evolutionarily Related to IL18BP and May Function As an IL-18 Receptor Chris S IL1R9 Is Evolutionarily Related to IL18BP and May Function as an IL-18 Receptor Chris S. Booker and David R. Grattan This information is current as J Immunol published online 23 November 2016 of September 28, 2021. http://www.jimmunol.org/content/early/2016/11/23/jimmun ol.1500648 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/11/23/jimmunol.150064 Material 8.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 23, 2016, doi:10.4049/jimmunol.1500648 The Journal of Immunology IL1R9 Is Evolutionarily Related to IL18BP and May Function as an IL-18 Receptor Chris S. Booker and David R. Grattan 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 Infor- Downloaded from mation 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 Journal of Immunology, 2017, 198: 000–000. http://www.jimmunol.org/ nterleukin-18 is a proinflammatory cytokine that activates A further anomaly regarding the IL-18 ligand/binding protein/ NF-kB, JNK, and p38-MAPK signaling pathways down- receptor system concerns the role of brain-produced IL-18, I stream of the IL-18R complex (1). IL-18 is constitutively which is constitutively present in select medial habenula (MHb) present in the circulation in the absence of an inflammatory neurons, principally located in the superior subnucleus (5, 6), with stimulus, and its activity is regulated by a natural antagonist, IL-18 strong projections to the interpeduncular nucleus (IPN). Currently binding protein (IL-18BP). A common evolutionary feature of there is no known role for MHb-produced IL-18, and studies ex- many cytokines is the presence of circulating soluble receptors, amining IL-18 receptor subunit distribution in the brain have not generated from transmembrane receptor mRNA through alternate shown a focus of receptor expression in the IPN (7–10); this by guest on September 28, 2021 exon usage, or by shedding extracellular portions of transmem- anomaly suggests the existence of a different receptor for IL-18. brane receptors upon ligand binding (2). Unlike other cytokine The idea that IL-18BP evolved from a transmembrane receptor binding proteins, IL-18BP is not derived from the transmembrane has been previously raised. In one of the papers describing the IL-18R subunits, and it shares little resemblance with either subunit; discovery of IL-18BP in 1999, Novick et al. (11) documented that both IL-18R subunits possess three Ig-like domains, and IL-18BP no reading frame existed that could generate a transmembrane possesses only one, and yet it shows higher affinity to IL-18 than receptor, noting, “It is possible that IL-18BP evolved from a pri- does the ligand-binding IL-18Ra-chain (3, 4). As such, IL-18BP is mordial cell-surface protein that lost its membrane-anchoring an oddity in the cytokine field, being a cytokine-specific inhibitory domain.” Similarities between IL-18BP and the inhibitory recep- binding protein unrelated to that cytokine’s transmembrane tor for IL-1 (IL-1R2, also known as IL-1RII) were noted by receptor. Novick et al. (11) and later explored by Watanabe et al. (12) who concluded “that IL-18BP and IL-1R2 had a common ancestral gene.” The IL-1 ligand and receptor families, to which IL18 and Centre for Neuroendocrinology, Department of Anatomy, University of Otago, IL1R2, respectively, belong, appear to have evolved via duplica- Dunedin 9054, New Zealand tion of both ligand and receptor genes, given the high degree of ORCID: 0000-0001-8095-7547 (C.S.B.). similarity among members of each group and their clustering Received for publication March 19, 2015. Accepted for publication November 2, 2016. along specific chromosomal loci (e.g., the IL-1 ligand family cluster at q13 and the IL-1R family cluster at q11.2 of chromo- This work was supported by Health Research Council of New Zealand Grants 08/076 and 11/1076. some 2 in humans). Thus, the hypothesis that IL18BP and IL1R2 Address correspondence and reprint requests to Dr. Chris S. Booker, Centre for had a common ancestral gene that underwent duplication fits well Neuroendocrinology, Department of Anatomy, University of Otago, P.O. Box 913, with the apparent proliferation of IL-1 ligand and receptor family Dunedin 9054, New Zealand. E-mail address: [email protected] members by gene duplication. However, because there is no evi- The online version of this article contains supplemental material. dence that IL-1R2 is capable of binding IL-18, if IL18BP and Abbreviations used in this article: BLAST, basic local alignment search tool; IL1R2 derived from a common ancestral gene, then IL18BP and IL-18BP, IL-18 binding protein; IL-18BPa, IL-18 binding protein isoform a; IL-1RAP, IL-1R accessory protein; IL-1RAPL, IL-1R accessory protein–like; IPN, interpeduncu- the regions of IL1R2 encoding extracellular portions of IL-1R2 lar nucleus; MHb, medial habenula; NUMA1, nuclear mitotic apparatus 1; PHI, pattern would need to have diverged sufficiently for the protein product of hit–initiated; PTPRD, protein tyrosine phosphatase receptor d; RNF121, ring finger IL18BP to consist of one Ig-like domain and bind IL-18 with high protein 121. affinity, and the protein product of IL1R2 to consist of three Ig-like Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 domains and not bind IL-18. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500648 2 IL1R9 AND IL18BP BINDING MOTIFS We hypothesized that the above anomalies could be overcome if alignment to make use of the crystal structures for ectromelia virus IL18BP were in fact related to a gene encoding a transmembrane IL-18BP (PDB ID 3F62) and Yaba-like disease virus IL-18BP (4EEC) receptor for IL-18 that has not been discovered or recognized to to guide alignment. Alignments were then passed through the MView visualization tool from the European Bioinformatics Institute to generate date. This would bring IL-18BP into line with other known cy- consensus sequences and residues involved in IL-18 binding or inhibition tokine inhibitors, which are typically related to, or arise from, a and were mapped as shown in Fig. 1 and Supplemental Fig. 1. transmembrane receptor for that cytokine. It would also open Three pattern hit–initiated (PHI) patterns were derived from the multiple new avenues of investigation by suggesting a ligand–receptor re- sequence alignment and consensus sequences: PHI pattern 1 included a key motif present at the 70% consensus level spanning many of the residues forming lationship between IL-18 and a previously unrecognized receptor. site A of poxvirus IL-18BP as defined by Krumm et al. (14, 16): Y-W-X(5,12)- Given the number of organisms in which entire genomes have F-X-E-X-L-X(5,7)-E (depicted in Fig. 1). PHI pattern 2 covered the same been sequenced, and annotation of protein-encoding regions in region as PHI pattern 1, but was derived from the 100% consensus sequence these genomes, it would be unlikely that a putative unrecognized by allowing for residues with similar physicochemical properties for those receptor for IL-18 would be an entirely undiscovered protein, but amino acids not conserved at the 100% level across the four proteins: Y-W-[ILV]- [ACFGHIKLMRTVWY]-[ACDEGHKNQRST]-X(0,7)-[ACDEGHKNQRST]- instead would be a known receptor that has not been recognized as [CDWHKNQRST]-[ACFGHIKLMRTVWY]-X-[DE]-[CDEHKNQRST]-L- being related to IL-18BP or involved in IL-18 action.
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