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

EMBO J. 2003 Oct 15;22(20):5480-90. doi: 10.1093/emboj/cdg524.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Carrier Proteins / metabolism*
  • Cell Membrane / immunology
  • Cell Membrane / physiology
  • Down-Regulation / drug effects
  • Humans
  • Interferon Type I / pharmacology
  • Interferon-alpha / pharmacology*
  • Ligands
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Peptide Fragments / metabolism
  • Phosphorylation
  • Protein Subunits / metabolism
  • Receptor, Interferon alpha-beta
  • Receptors, Interferon / deficiency
  • Receptors, Interferon / genetics
  • Receptors, Interferon / physiology*
  • Recombinant Proteins
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Signal Transduction / drug effects
  • Ubiquitin-Protein Ligases
  • beta-Transducin Repeat-Containing Proteins*


  • Carrier Proteins
  • FBXW11 protein, human
  • Fbxw1b protein, mouse
  • IFNAR1 protein, human
  • IFNAR2 protein, human
  • Ifnar1 protein, mouse
  • Ifnar2 protein, mouse
  • Interferon Type I
  • Interferon-alpha
  • Ligands
  • Membrane Proteins
  • Peptide Fragments
  • Protein Subunits
  • Receptors, Interferon
  • Recombinant Proteins
  • beta-Transducin Repeat-Containing Proteins
  • Receptor, Interferon alpha-beta
  • SKP Cullin F-Box Protein Ligases
  • Ubiquitin-Protein Ligases