Computational identification, cloning, and characterization of IL-1R9, a novel interleukin-1 receptor-like gene encoded over an unusually large interval of human chromosome Xq22.2-q22.3.
The Interleukin-1 receptor (IL-1R) and Toll signaling pathways share the evolutionarily conserved Toll homology domain (THD), which is a critical component in the signaling cascade of the host defense responses to infection and inflammation. Our initial genomic database searches uncovered a novel THD signature sequence between DNA markers DXS87 and DXS366. The feasibility of subsequently applying a coordinated computational approach, including various exon-finding programs, homology-based searches, and receptor profile searches, in revealing the exons encoding this novel IL-1R family member is described. IL-1R9 shows restricted expression in fetal brain and is highly homologous to IL1RAPL (A. Carrie et al., 1999 Nat. Genet. 23: 25-31), which is reportedly involved in nonsyndromic X-linked mental retardation. These genes are scattered over separate genomic intervals in excess of 1.0 Mb and encode receptors with extended C-terminal tails. In our functional NF-kappaB reporter assays, IL1RAPL, IL-1R9, or versions lacking the extended C-terminal sequences failed in responding either to IL-1 directly or to IL-18 when various permutations of IL-18R ectodomain chimeras were fused to their cytoplasmic domains. Evolutionary sequence analyses reinforce our conclusion that these novel orphan receptors probably form a functionally distinct subset of the IL-1R superfamily.
Sana
T R
TR
Department of Molecular Biology, DNAX Research Institute, 901 California Avenue, Palo Alto, California 94304-1104, USA. sana@dnax.org
Debets
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Timans
J C
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Bazan
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JF
Kastelein
R A
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D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D019143:Evolution, Molecular; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007375:Interleukin-1 / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D012984:Software; D014960:X Chromosome
D007375:Interleukin-1; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I