USP18 establishes the transcriptional and anti-proliferative interferon α/β differential
- 28 August 2012
- journal article
- research article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 446 (3), 509-516
- https://doi.org/10.1042/bj20120541
Abstract
Type I IFNs (interferons) are pathogen-induced immunoregulatory cytokines that exert anti-viral and anti-proliferative activities through binding to a common cell-surface receptor. Among the 17 human IFN subtypes, IFNβ binds the IFNAR (IFNα receptor) 1/IFNAR2 receptor chains with particularly high affinity and is especially potent in select bioactivities (e.g. anti-proliferative and pro-apoptotic) when compared with IFNα2. However, no molecular basis has been ascribed to this differential action, since the two ligands are equipotent in immediate early signalling events. In the present study we report that IFNβ induces Stat (signal transducer and activator of transcription) phosphorylation and transcriptional activation of ISGs (interferon-stimulated genes), including two genes with pro-apoptotic functions, for a considerably longer time frame than does IFNα2. We show that the diversification of α2/β responses progressively builds up at the receptor level as a result of accumulating USP18 (ubiquitin specific protease 18), itself an ISG, which exerts its negative feedback action by taking advantage of the weakness of IFNα2 binding to the receptor. This represents a novel type of signalling regulation that diversifies the biological potential of IFNs α and β.This publication has 43 references indexed in Scilit:
- Constitutive Type I Interferon Modulates Homeostatic Balance through Tonic SignalingImmunity, 2012
- Evolutionary genetic dissection of human interferonsThe Journal of Experimental Medicine, 2011
- Structural Linkage between Ligand Discrimination and Receptor Activation by Type I InterferonsCell, 2011
- The Interferon Stimulated Gene 54 Promotes ApoptosisOnline Journal of Public Health Informatics, 2011
- Ligand-Stimulated Downregulation of the Alpha Interferon Receptor: Role of Protein Kinase D2Molecular and Cellular Biology, 2011
- Interferon signaling and treatment outcome in chronic hepatitis CProceedings of the National Academy of Sciences of the United States of America, 2008
- Comparable potency of IFNα2 and IFNβ on immediate JAK/STAT activation but differential down-regulation of IFNAR2Biochemical Journal, 2007
- Tissue-Specific and Inducer-Specific Differential Induction of ISG56 and ISG54 in MiceJournal of Virology, 2007
- Phosphoinositide 3-kinase regulates a subset of interferon-alpha-stimulated genesExperimental Cell Research, 2007
- UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activityThe EMBO Journal, 2006