INTERFERON-ALPHA (IFN-ALPHA) SIGNALING IN CELLS EXPRESSING THE VARIANT FORM OF THE TYPE-I IFN RECEPTOR

Two different type I interferon receptors (IFN-R) have been described: the normal and the variant receptors. The a subunit of the Type I IFN -R has a molecular mass of 110 kDa in cells expressing normal and vari ant receptors. The beta subunit has a molecular mass of approximately 100 kDa in cells that express normal receptors and 55 kDa in cells exp ressing the variant form of the receptor. The IFN alpha-resistant U-93 7 cell line expresses variant receptors and fails to down-regulate and phosphorylate the alpha subunit on tyrosine residues. We report that two other myelomonocytic cell lines, YK-M2 and ML-2, also expressing t he variant form of the receptor, fail to down-regulate and phosphoryla te the a subunit on tyrosine residues. However, YK-M2 and ML-2 cells a re sensitive to the antiproliferative and antiviral effects of IFN alp ha 2, indicating that phosphorylation of the a subunit is not necessar y to elicit an IFN alpha response and that expression of variant recep tors is not a source of IFN alpha resistance. We also determined if ot her proteins involved in the IFN alpha signal transduction pathway had a different phosphorylation pattern. Treatment of cells expressing va riant receptors induced tyrosine phosphorylation of the p135(tyk2) tyr osine kinase, and the three interferon-stimulated gene factor 3 alpha (ISGFS3 alpha) polypeptides (p113, p91, and p84), albeit at lower leve ls. These results indicate that cells expressing either form of the Ty pe I IFN-R phosphorylate a similar set of proteins, with the exception of the alpha subunit.