SCFHOS ubiquitin ligase mediates the ligand-induced down-regulation of the interferon- receptor

Open Access
Publisher Website
Google Scholar
Abstract
Down‐regulation of activated signaling receptors in response to their ligands plays a key role in restricting the extent and duration of the signaling. Mechanisms underlying down‐regulation of the type I interferon receptor consisting of IFNAR1 and IFNAR2 subunits remain largely unknown. Here we show that IFNAR1 interacts with the Homolog of Slimb (HOS) F‐box protein in a phosphorylation‐dependent manner, and that this interaction is promoted by interferon α (IFNα). IFNAR1 is ubiquitinated by the Skp1‐Cullin1‐HOS‐Roc1 (SCFHOS) ubiquitin ligase in vitro. HOS expression and activities are required for IFNα‐stimulated ubiquitination of IFNAR1, endocytosis of the type I interferon receptor, down‐regulation of IFNAR1 levels, and IFNAR1 proteolysis via the lysosomal pathway. Furthermore, modulations of HOS activities affect the extent of Stat1 phosphorylation and Stat‐mediated transcriptional activities as well as the extent of antiproliferative effects of type I interferons. These findings characterize SCFHOS as an E3 ubiquitin ligase that is essential for ubiquitination, proteolysis and down‐regulation of IFNAR1, and implicate HOS in the regulation of cellular responses to IFNα.