STAM Interaction with Hrs Controls JAK/STAT Activation by Interferon-α at the Early Endosome

Activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway by type I interferons (IFN) requires clathrin-dependent endocytosis of the IFN-α/β receptor (IFNAR). The molecular machinery that brings about the selective activation of IFN-α/β-induced JAK/STAT signaling on endosomes remains unknown. Here we show that the constitutive association of STAM with IFNAR1 and the TYK2 Janus kinase at the plasma membrane prevents the activation of TYK2 by type I IFNs. IFN-α stimulated endocytosis leads to the interaction of IFNAR1 with Hrs on early endosomes, which then relieves TYK2 inhibition by STAM and thereby allows for TYK2 and IFNAR signaling. In contrast, IFN-β stimulation results in sorting of IFNAR to a distinct endosomal subdomain where the receptor is activated independently from Hrs. Our results identify the molecular machinery that controls the spatiotemporal activation of TYK2 and establish the central role of endosomal sorting in the differential regulation of JAK/STAT signaling by IFN-α and IFN-β.