The intracellular domain of interferon-α receptor 2c (IFN-αR2c) chain is responsible for Stat activation

Type I IFNs activate the Jak-Stat signal transduction pathway. The IFN-alpha receptor 1 (IFN-alpha R1) subunit and two splice variants of the IFN-alpha R2 subunit, IFN-alpha R2c and IFN-alpha R2b, are involved in ligand binding. All these receptors have been implicated in cytokine signaling and, specifically in Stat recruitment. To evaluate the specific contribution of each receptor subunit to Stat recruitment we employed chimeric receptors with the extracellular domain of either IFN-gamma R2 or IFN-gamma R1 fused to the intracellular domains of IFN-alpha R1, IFN-alpha R2b, and IFN-alpha R2c. These chimeric receptors were expressed in hamster cells. Because human IFN-gamma exhibits no activity on hamster cells, the use of the human IFN-gamma receptor extracellular domains allowed us to avoid the variable cross-species activity of the type I IFNs and eliminate the possibility of contributions of endogenous type I IFN receptors into the Stat recruitment process. We demonstrate that Stat recruitment is solely a function of the IFN-alpha R2c intracellular domain. When chimeric receptors with the human IFN-gamma R1 extracellular domain and various human IFN-alpha receptor intracellular domains were expressed in hamster cells carrying the human IFN-gamma R2 subunit, only the IFN-alpha R2c subunit was capable of supporting IFN-gamma signaling as measured by MHC class I induction, antiviral protection, and Stat activation. Neither the IFN-alpha R2b nor the IFN-alpha R1 intracellular domain was able to recruit Stats or support IFN-gamma-induced biological activities. Thus, the IFN-alpha R2c intracellular domain is necessary and sufficient to activate Stat1, Stat2, and Stat3 proteins.