The Antiviral Action of Interferon Is Potentiated by Removal of the Conserved IRTAM Domain of the IFNAR1 Chain of the Interferon α/β Receptor: Effects on JAK-STAT Activation and Receptor Down-regulation

Abstract

The first cloned chain (IFNAR1) of the human interferon-α (IFNα) receptor acts as a species-specific transducer for type I IFN action when transfected into heterologous mouse cells. Stably transfected mouse L929 cell lines expressing truncation mutants of the intracellular domain of the human IFNAR1 chain were tested for biological responses to human IFNα. Deletion of the intracellular domain resulted in a complete loss of sensitivity to the biological activity of human IFN but markedly increased IFNAR1 cell surface expression, demonstrating that the intracellular domain is required for biological function and contains a domain that negatively regulates its cell surface expression. Removal of the conserved membrane distal 16-amino-acid IRTAM (InterferonReceptorTyrosineActivationMotif) sequence: (1) increased sensitivity to IFNα's antiviral activity, (2) increased the rapid IFNα-dependent formation of STAT-containing DNA-binding complexes, (3) prolonged tyrosine phosphorylation kinetics of the JAK-STAT pathway, and (4) blocked the IFN-dependent down-regulation of the IFNAR1 chain. These results indicate that the IRTAM negatively regulates signaling events required for the induction of IFN's biological actions via regulating receptor down-regulation