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 ev olutionarily conserved Toll homology domain (THD), which is a critical comp onent in the signaling cascade of the host defense responses to infection a nd inflammation. Our initial genomic database searches uncovered a novel TH D signature sequence between DNA markers DXS87 and DXS366. The feasibility of subsequently applying a coordinated computational approach, including va rious 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 Not. 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 Rib an d encode receptors with extended C-terminal tails. In our functional NF-kap paB reporter assays, IL1RAPL, IL-1R9, or versions lacking the extended C-te rminal sequences failed in responding either to IL-1 directly or to IL-18 w hen various permutations of IL-18R ectodomain chimeras were fused to their cytoplasmic domains. Evolutionary sequence analyses reinforce our conclusio n that these novel orphan receptors probably form a functionally distinct s ubset of the IL-1R superfamily. (C) 2000 Academic Press.