TRANSMEMBRANE SIGNALING BY THE ALPHA-SUBUNIT OF THE TYPE-I INTERFERONRECEPTOR IS ESSENTIAL FOR ACTIVATION OF THE JAK KINASES AND THE TRANSCRIPTIONAL FACTOR ISGF3

The Type I interferon (IFN) receptor has a multisubunit structure. The component of the receptor that has been most thoroughly studied is th e alpha subunit. Expression of the alpha subunit in mouse L-929 cells confers antiviral response to human IFN alpha 8, but not to human IFN alpha 2 or IFN beta. This antiviral effect is observed without a signi ficant increase in IFN binding. It has not been determined why mouse c ells expressing the human alpha subunit show different response to the antiviral activity of distinct human Type I IFNs. In this report, we demonstrate that the response to human Type I IFNs in mouse cells expr essing the alpha subunit is dependent on cross-binding to the mouse re ceptor. This is supported by the finding that human IFN alpha 8, but n ot human IFN alpha 2, cross-binds to the mouse receptor even in the ab sence of expression of the human alpha subunit. We also demonstrate th at only mouse cells expressing the human alpha subunit are able to tyr osine-phosphorylate p135(tyk2) and JAK-1 and to form the ISGF3 complex in response to human IFN alpha 8. These results demonstrate that the alpha subunit is essential for IFN alpha signaling through the JAK kin ases and ISGF3.