title: Small Ubiquitin-like Modifier Alters IFN Response.
abstract: IFNs orchestrate immune defense through induction of hundreds of genes. Small ubiquitin-like modifier (SUMO) is involved in various cellular functions, but little is known about its role in IFN responses. Prior work identified STAT1 SUMOylation as an important mode of regulation of IFN-γ signaling. In this study, we investigated the roles of SUMO in IFN signaling, gene expression, protein stability, and IFN-induced biological responses. We first show that SUMO overexpression leads to STAT1 SUMOylation and to a decrease in IFN-induced STAT1 phosphorylation. Interestingly, IFNs exert a negative retrocontrol on their own signaling by enhancing STAT1 SUMOylation. Furthermore, we show that expression of each SUMO paralog inhibits IFN-γ-induced transcription without affecting that of IFN-α. Further, we focused on IFN-induced gene products associated to promyelocytic leukemia (PML) nuclear bodies, and we show that neither IFN-α nor IFN-γ could increase PML and Sp100 protein expression because they enhanced their SUMO3 conjugation and subsequent proteasomal degradation. Because it is known that SUMO3 is important for the recruitment of RING finger protein 4, a poly-SUMO-dependent E3 ubiquitin ligase, and that PML acts as a positive regulator of IFN-induced STAT1 phosphorylation, we went on to show that RING finger protein 4 depletion stabilizes PML and is correlated with a positive regulation of IFN signaling. Importantly, inhibition of IFN signaling by SUMO is associated with a reduction of IFN-induced apoptosis, cell growth inhibition, antiviral defense, and chemotaxis. Conversely, inhibition of SUMOylation results in higher IFN-γ-induced STAT1 phosphorylation and biological responses. Altogether, our results uncover a new role for SUMO in the modulation of IFN response.
authors.affiliation: INSERM Unité Mixte de Recherche S 1124, Université Paris Descartes, 75006 Paris, France.
authors.forename: Ghizlane
authors.initials: G
authors.lastname: Maarifi
authors.affiliation: INSERM Unité Mixte de Recherche S 1124, Université Paris Descartes, 75006 Paris, France.
authors.forename: Mohamed Ali
authors.initials: MA
authors.lastname: Maroui
authors.affiliation: INSERM Unité Mixte de Recherche S 1124, Université Paris Descartes, 75006 Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Dutrieux
authors.affiliation: INSERM Unité Mixte de Recherche S 1124, Université Paris Descartes, 75006 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Dianoux
authors.affiliation: INSERM Unité Mixte de Recherche S 1124, Université Paris Descartes, 75006 Paris, France sebastien.nisole@inserm.fr mounira.chelbi-alix@parisdescartes.fr.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Nisole
authors.affiliation: INSERM Unité Mixte de Recherche S 1124, Université Paris Descartes, 75006 Paris, France sebastien.nisole@inserm.fr mounira.chelbi-alix@parisdescartes.fr.
authors.forename: Mounira K
authors.initials: MK
authors.lastname: Chelbi-Alix
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D001324:Autoantigens; D016898:Interferon-alpha; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D025842:SUMO-1 Protein; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; C066642:SP100 protein, human; C070576:PML protein, human; D007371:Interferon-gamma; D007372:Interferons