USP18 establishes the transcriptional and anti-proliferative interferon α/β differential

Type I IFNs (interferons) are pathogen-induced immunoregulatory cytokines that exert anti-viral and anti-proliferative activities through binding to a common cell-surface receptor. Among the 17 human IFN subtypes. IFN beta binds the IFNAR (IFN alpha receptor) 1/IFNAR2 receptor chains with particularly high affinity and is especially potent in select bioactivities (e.g. anti-proliferative and pro-apoptotic) when compared with IFN alpha 2. However, no molecular basis has been ascribed to this differential action, since the two ligands are equipotent in immediate early signalling events. In the present study we report that IFN beta induces Stat (signal transducer and activator of transcription) phosphorylation and transcriptional activation of ISGs (interferon-stimulated genes), including two genes with pro-apoptotic functions, for a considerably longer time frame than does IFN alpha 2. We show that the diversification of alpha 2/beta responses progressively builds up at the receptor level as a result of accumulating USP18 (ubiquitin-specific protease 18), itself an ISG, which exerts its negative feedback action by taking advantage of the weakness of IFN alpha 2 binding to the receptor. This represents a novel type of signalling regulation that diversifies the biological potential of IFNs alpha and beta.