THE ANTIVIRAL ACTION OF INTERFERON IS POTENTIATED BY REMOVAL OF THE CONSERVED IRTAM DOMAIN OF THE IFNAR1 CHAIN OF THE INTERFERON-ALPHA BETARECEPTOR - EFFECTS ON JAK-STAT ACTIVATION AND RECEPTOR DOWN-REGULATION/

The first cloned chain (IFNAR1) of the human interferon-alpha (IFN alp ha) receptor acts as a species-specific transducer for type I IFN acti on when transfected into heterologous mouse cells. Stably transfected mouse L929 cell lines expressing truncation mutants of the intracellul ar domain of the human IFNAR1 chain were tested for biological respons es to human IFN alpha. Deletion of the intracellular domain resulted i n a complete loss of sensitivity to the biological activity of human I FN but markedly increased IFNAR1 cell surface expression. demonstratin g that the intracellular domain is required for biological function an d contains a domain that. negatively regulates its cell surface expres sion. Removal of the conserved membrane distal 18-amino-acid IRTAM (In terferon Receptor Tyrosine Activation Motif) sequence: (1) increased s ensitivity to IFN alpha's antiviral activity, (2) increased the rapid IFN alpha-dependent formation of STAT-containing DNA-binding complexes , (3) prolonged tyrosine phosphorylation kinetics of the JAK-STAT path way, and (4) blocked the IFN-dependent down-regulation of the IFNAR1 c hain. These results indicate that the IRTAM negatively regulates signa ling events required for the induction of IFN's biological actions via regulating receptor down-regulation. (C) 1998 Academic Press.