Identification and characterization of two members of a novel class of the interleukin-1 receptor (IL-1R) family. Delineation of a new class of IL-1R-related proteins based on signaling.

Two novel members of the interleukin-1 receptor (IL-1R) family, identified by homology searches of human genomic sequence data bases, are described. The genes have been named according to their structural features: TIGIRR-1 (three immunoglobulin domain-containing IL-1 receptor-related) and TIGIRR-2. TIGIRR-2 has recently been identified as causing mental retardation when mutated (Carrie, A., Jun, L., Bienvenu, T., Vinet, M. C., McDonell, N., Couvert, P., Zemni, R., Cardona, A., Van Buggenhout, G., Frints, S., Hamel, B., Moraine, C., Ropers, H. H., Strom, T., Howell, G. R., Whittaker, A., Ross, M. T., Kahn, A., Fryns, J. P., Beldjord, C., Marynen, P., and Chelly, J. (1999) Nat. Genet. 23, 25-31) and called IL1RAPL, a name we will also use henceforth. Neither receptor alone was able to mediate transcriptional activation of NF-kappaB in response to IL-1alpha, IL-1beta, or IL-18. In order to begin to elucidate the function of these and other orphan IL-1R family members, we have developed a functional assay utilizing a panel of chimeric receptors containing the extracellular and transmembrane domains of either type I IL-1R or IL-1R accessory protein (AcP) coupled to the cytoplasmic domains of all family members. Coexpression of each IL-1R chimera with each AcP chimera and an NF-kappaB-responsive reporter demonstrated that the cytoplasmic domains could be classified as IL-1R-like, AcP-like, or neither. Any IL-1R-like cytoplasmic domain could cooperate with any AcP-like cytoplasmic domain. The TIGIRR-1 and IL1RAPL cytoplasmic domains, however, were unable to signal as either IL-1R-like or AcP-like components, suggesting that they function as a new class of receptors within this family.