SCF(HOS) ubiquitin ligase mediates the ligand-induced down-regulation of the interferon-alpha receptor.

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 alpha (IFNalpha). IFNAR1 is ubiquitinated by the Skp1-Cullin1-HOS-Roc1 (SCF(HOS)) ubiquitin ligase in vitro. HOS expression and activities are required for IFNalpha-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 SCF(HOS) 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 IFNalpha.
Mesh Terms:
3T3 Cells, Animals, Carrier Proteins, Cell Membrane, Down-Regulation, Humans, Interferon Type I, Recombinant, Interferon-alpha, Ligands, Membrane Proteins, Mice, Mice, Knockout, Peptide Fragments, Phosphorylation, Protein Subunits, Receptor, Interferon alpha-beta, Receptors, Interferon, SKP Cullin F-Box Protein Ligases, Signal Transduction, Ubiquitin-Protein Ligases, beta-Transducin Repeat-Containing Proteins
EMBO J.
Date: Oct. 15, 2003
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