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.
Kumar
K G Suresh
KG
Department of Animal Biology, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6046, USA.
Tang
Weigang
W
Ravindranath
Abhilash K
AK
Clark
William A
WA
Croze
Ed
E
Fuchs
Serge Y
SY
D016475:3T3 Cells; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000276:immunology / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology*; D008024:Ligands; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases; D044844:beta-Transducin Repeat-Containing Proteins
D002352:Carrier Proteins; C471645:FBXW11 protein, human; C486774:Fbxw1b protein, mouse; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; C508032:Ifnar1 protein, mouse; C508034:Ifnar2 protein, mouse; D007370:Interferon Type I; D016898:Interferon-alpha; D008024:Ligands; D008565:Membrane Proteins; D010446:Peptide Fragments; D021122:Protein Subunits; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D053633:Receptor, Interferon alpha-beta; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases