Identification of Distinct Signaling Pathways Leading to the Phosphorylation of Interferon Regulatory Factor 3

Servant, Marc J.; Oever, Benjamin ten; Page, Cécile Le; Conti, Lucia; Gessani, Sandra; Julkunen, Ilkka; Lin, Rongtuan; Hiscott, John

doi:10.1074/jbc.m007790200

Cited by 181 publications

(213 citation statements)

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“…Gene clusters: 1, metabolism; 2, protein synthesis, modification and secretion; 3, ion channels, ion transporters and related proteins; 4, hormones, growth factors and related genes; 5, cytokines, chemokines and related receptors; 6, cytokine signal transduction; 7, MHC and related genes; 8, cell adhesion, cytoskeleton and related genes; 9, transcription factors and related proteins; 10, RNA synthesis, editing and splicing factors; 11, cell cycle; 12, defence/repair; 13, apoptosis and ER stress response and related genes; 14, antiviral response; 15, miscellaneous; 16, hypothetical proteins; 17, not classified viral infection and cytokine treatment (Tables S2 and S3). Activation of TLR-3 usually results in stimulation of IκB-related kinase and TBK-1 (TANK-binding kinase), leading to activation of transcription factors such as immune regulatory factor 3 (IRF-3) (regulated at the post-transcriptional level) [22,23] and NFκB, which in turn results in Fig. 4 Stimulation of genes involved in inflammation (a-c), transcription (d-e), and apoptosis and antiviral effects (f-g) by coxsackievirus B5 (CBV-5) and cytokines, IL-1β+IFN-γ, in human islets.…”

Section: Resultsmentioning

confidence: 99%

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Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

et al. 2005

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Aims/hypothesis: It is thought that enterovirus infections initiate or facilitate the pathogenetic processes leading to type 1 diabetes. Exposure of cultured human islets to cytolytic enterovirus strains kills beta cells after a protracted period, suggesting a role for secondary virusinduced factors such as cytokines. Methods: To clarify the molecular mechanisms involved in virus-induced beta cell destruction, we analysed the global pattern of gene expression in human islets. After 48 h, RNA was extracted from three independent human islet preparations infected with coxsackievirus B5 or exposed to interleukin 1β (50 U/ml) plus interferon γ (1,000 U/ml), and gene expression profiles were analysed using Affymetrix HG-U133A gene chips, which enable simultaneous analysis of 22,000 probe sets. Results: As many as 13,077 genes were detected in control human islets, and 945 and 1293 single genes were found to be modified by exposure to viral infection and the indicated cytokines, respectively. Four hundred and eighty-four genes were similarly modified by the cytokines and viral infection. Conclusions/ interpretation: The large number of modified genes observed emphasises the complex responses of human islet cells to agents potentially involved in insulitis. Notably, both cytokines and viral infection significantly (p<0.02) increased the expression of several chemokines, the cytokine IL-15 and the intercellular adhesion molecule ICAM-1, which might contribute to the homing and activation of mononuclear cells in the islets during infection and/or an early autoimmune response. The present results provide novel insights into the molecular mechanisms involved in viral-and cytokine-induced human beta cell dysfunction and death.

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Section: Resultsmentioning

confidence: 99%

“…IFIT1: 2 and 4 interferon-induced protein with tetratricopeptide repeats 1, 2 and 4 . IFITM1: interferon-induced transmembrane protein 1 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) . IFNB1: interferon β1, fibroblast .…”

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confidence: 99%

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

et al. 2005

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“…As shown in Fig. 1A, treatment of cells with small concentration (1 M) of MG-132 significantly diminished the degradation of IRF-3 following virus infection and induced the accumulation of C-terminal hyperphosphorylated forms of IRF-3 (compare lanes 3-5 with lanes 8 -10), which migrate more slowly on SDS-gel (17,38). Higher concentrations of MG-132 totally blocked IRF-3 degradation but also inhibited the activation of the latter following virus infection (data not shown).…”

Section: Virus Infection Results In Proteasome-dependent Degradation mentioning

confidence: 99%

“…These studies have led to the characterization of new inducers of IRF-3 activity as well as the intracellular signaling pathways leading to IRF-3 activation (38,42,43,55,56). Notably, two IKK homologs, IKKi and TBK1, were shown to be involved in IRF-3 phosphorylation and activation (12)(13)(14)(15)(16)57).…”

Section: Discussionmentioning

confidence: 99%

“…Commercial Abs were from the following suppliers: anti-IRF-3 Abs specific for human and rodent species were from Immuno-Biological Laboratories (IBL) and Zymed Laboratories, respectively; anti-IKKE Ab (IMG-270A) (that recognize as well TBK1) was from Imgenex; anti-ubiquitin mAb (clone P4D1) and mAb to MYC were from Santa Cruz Biotechnology; mAbs to hemagglutinin (HA) (clone HA-7) and Flag epitopes and ␤-actin (clone AC-74) were from Sigma-Aldrich. Plasmids encoding for Flag-wtIRF-3, Flag-IRF3 5D, Flag-IRF-3 J2D, Flag-IRF-3 7D, Flag-IRF-3 5A, and Myc-wtIRF-3 have been described (17,38). Plasmids encoding for Flag-IKKiwt and the dominant-negative version Flag-IKKi K38A were gifts of Dr. R. Lin (McGill University, Montreal, Quebec, Canada).…”

Section: Reagent Abs and Plasmidsmentioning

confidence: 99%

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Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Bibeau-Poirier¹,

Gravel²,

Clément³

et al. 2006

The Journal of Immunology

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Activation of the innate arm of the immune system following pathogen infection relies on the recruitment of latent transcription factors involved in the induction of a subset of genes responsible for viral clearance. One of these transcription factors, IFN regulatory factor 3 (IRF-3), is targeted for proteosomal degradation following virus infection. However, the molecular mechanisms involved in this process are still unknown. In this study, we show that polyubiquitination of IRF-3 increases in response to Sendai virus infection. Using an E1 temperature-sensitive cell line, we demonstrate that polyubiquitination is required for the observed degradation of IRF-3. Inactivation of NEDD8-activating E1 enzyme also results in stabilization of IRF-3 suggesting the NEDDylation also plays a role in IRF-3 degradation following Sendai virus infection. In agreement with this observation, IRF-3 is recruited to Cullin1 following virus infection and overexpression of a dominant-negative mutant of Cullin1 significantly inhibits the degradation of IRF-3 observed in infected cells. We also asked whether the C-terminal cluster of phosphoacceptor sites of IRF-3 could serve as a destabilization signal and we therefore measured the half-life of C-terminal phosphomimetic IRF-3 mutants. Interestingly, we found them to be short-lived in contrast to wild-type IRF-3. In addition, no degradation of IRF-3 was observed in TBK1−/− mouse embryonic fibroblasts. All together, these data demonstrate that virus infection stimulates a host cell signaling pathway that modulates the expression level of IRF-3 through its C-terminal phosphorylation by the IκB kinase-related kinases followed by its polyubiquitination, which is mediated in part by a Cullin-based ubiquitin ligase.

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Transcriptional activation induced in macrophages by Toll‐like receptor (TLR) ligands: from expression profiling to a model of TLR signaling

et al. 2004

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Toll-like receptors (TLR) sense microbial compounds and bridge innate and adaptive immunity by activation of antigen-presenting cells. TLR-induced signaling via intracellular adaptor molecules, including MyD88 and TRIF, drives transcriptional activation of genes including pro-inflammatory cytokines and cell activation markers. To globally assess the activation programs triggered by individual TLR in macrophages, we used microarray-based gene expression profiling of the murine macrophage cell line RAW264.7. Here we describe that the TLR4 ligand LPS more strongly modulates gene expression compared to ligands for TLR 2, 3, 7, and 9. Taking advantage of the known dependency of TLR on given adaptor molecules, we operationally define sets of MyD88 and TRIF "private" genes. We conclude with a TLR signaling model that incorporates both negative and synergistic interactions of MyD88-and TRIF-controlled signaling pathways as deduced from the microarray data presented.

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Identification of Distinct Signaling Pathways Leading to the Phosphorylation of Interferon Regulatory Factor 3

Cited by 181 publications

References 46 publications

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Transcriptional activation induced in macrophages by Toll‐like receptor (TLR) ligands: from expression profiling to a model of TLR signaling

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