An Alu cassette in the cytoplasmic domain of an interferon receptor subunit

All the cloned subunits of interferon receptors (IFNRs) belong to the type II cytokine receptor family (CRF2). Although three members of CRF2 encoded on human chromosome 21 share a 50 amino acid cytoplasmic homology domain (the IRH2 domain), a fourth subunit, the second cloned chain of the type I IFNR (IFNIR-2), contains a juxtamembrane 20 amino acid stretch of high similarity to the IRH2 domain that stops abruptly. Comparison of the membrane-distal portion of the IFNIR-2 cytoplasmic domain with sequence databases revealed a very high similarity to Alu repeat sequences. We provide evidence that all but 18 amino acids of the predicted cytoplasmic domain of the IFNIR-2 chain are encoded by an Alu cassette in its antisense orientation. Incorporation of an Alu cassette into the receptor chain is proposed to occur by a splicing mechanism. All previous well-characterized examples of insertion of an antisense Alu cassette into an open reading frame have involved alternative splicing. Thus, we predict the existence of an alternatively spliced product of the IFNIR-2 chain with a substantially different cytoplasmic domain.