STAM and Hrs interact sequentially with IFN-alpha Receptor to control spatiotemporal JAK-STAT endosomal activation

Abstract

Activation of the JAK-STAT pathway by type I interferons (IFNs) requires clathrin-dependent endocytosis of the IFN-alpha and -beta receptor (IFNAR), indicating a role for endosomal sorting in this process. The molecular machinery that brings the selective activation of IFN-alpha/beta-induced JAK-STAT signalling on endosomes remains unknown. Here we show that the constitutive association of STAM with IFNAR1 and TYK2 kinase at the plasma membrane prevents TYK2 activation by type I IFNs. IFN-alpha-stimulated IFNAR endocytosis delivers the STAM-IFNAR complex to early endosomes where it interacts with Hrs, thereby relieving TYK2 inhibition by STAM and triggering signalling of IFNAR at the endosome. In contrast, when stimulated by IFN-beta, IFNAR signalling occurs independently of Hrs as IFNAR is sorted to a distinct endosomal subdomain. Our results identify the molecular machinery that controls the spatiotemporal activation of IFNAR by IFN-alpha and establish the central role of endosomal sorting in the differential regulation of JAK-STAT signalling by IFN-alpha and IFN-beta. Zanin, Viaris de Lesegno et al. identify what controls the endosomal activation of the IFNAR receptor by IFN-alpha and establish a central role for endosomal sorting via STAM and Hrs in the differential regulation of JAK-STAT signalling by IFN-alpha and IFN-beta.