MUTANT U5A CELLS ARE COMPLEMENTED BY AN INTERFERON-ALPHA-BETA RECEPTOR SUBUNIT GENERATED BY ALTERNATIVE PROCESSING OF A NEW MEMBER OF A CYTOKINE RECEPTOR GENE-CLUSTER

The cellular receptor for the alpha/beta interferons contains at least two components that interact with interferon. The ifnar1 component is well characterized and a putative ifnar2 cDNA has recently been ident ified. We have cloned the gene for ifnar2 and show that it produces fo ur different transcripts encoding three different polypeptides that ar e generated by exon skipping, alternative splicing and differential us e of polyadenylation sites. One polypeptide is likely to be secreted a nd two are transmembrane proteins with identical extracellular and tra nsmembrane domains but divergent cytoplasmic tails of 67 and 251 amino acids. A mutant cell line U5A, completely defective in IFN-alpha beta binding and response, has been isolated and characterized. Expression in U5A cells of the polypeptide with the long cytoplasmic domain reco nstitutes a functional receptor that restores normal interferon bindin g, activation of the JAK/STAT signal transduction pathway, interferon- inducible gene expression and antiviral response. The IFNAR2 gene maps at 0.5 kb from the CRFB4 gene, establishing that together IFNAR2, CRF B4, IFNAR1 and AF1 form a cluster of class II cytokine receptor genes on human chromosome 21.