Virus-Dependent Phosphorylation of the IRF-3 Transcription Factor Regulates Nuclear Translocation, Transactivation Potential, and Proteasome-Mediated Degradation

Lin, Rongtuan; Heylbroeck, Christophe; Pitha, Paula M.; Hiscott, John

doi:10.1128/mcb.18.5.2986

Cited by 851 publications

(1,010 citation statements)

References 71 publications

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“…These results are in agreement with the results of transfection experiments, suggesting that the protein components of the retarded complexes may be involved in viral induction of the NOXA promoter. The slower and faster migrating complexes contain IRF-1 and IRF-3, respectively, as indicated by specific inhibition of complex formation following preincubation of the EMSA reaction mix with anti-IRF-1 or anti-phospho-IRF-3 (the activated form of IRF-3 present during virus infection as described previously (Lin et al, 1998)), antibodies, respectively (Figure 5b). Together, these results suggest that SV infection induces the binding of IRF-1 and phospho-IRF-3 at the IRF-E site of the NOXA promoter, leading to the transcription of NOXA.…”

Section: Inactivation Of the Transcriptional Activity Of Wt-p53 In Resupporting

confidence: 62%

Single-stranded RNA viruses inactivate the transcriptional activity of p53 but induce NOXA-dependent apoptosis via post-translational modifications of IRF-1, IRF-3 and CREB

et al. 2006

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Section: Inactivation Of the Transcriptional Activity Of Wt-p53 In Resupporting

confidence: 62%

Single-stranded RNA viruses inactivate the transcriptional activity of p53 but induce NOXA-dependent apoptosis via post-translational modifications of IRF-1, IRF-3 and CREB

et al. 2006

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“…The pcDNA3.1zeo-flag-I B␣2N plasmid was generated by subcloning the I B␣2N cDNA from the SVK3-I B␣2N constructs. Plasmids encoding Myc-IKK␣, Flag-IKK␤wt, and Flag-IKK␤DN were previously described (39). The pcDNA3.1zeo-myc-cRel plasmid was generated by cloning the PCR-amplified forward primer 5Ј-ATA TAA GCT TAG CGG AGC CAT GGC CTC CGG TGC GTA TAA-3Ј, reverse primer 5Ј-ATC GGA ATT CTA CAA AAT GCT GCA TCT ATA T-3Ј cRel sequence into the EcoRI/HindIII sites of the pcDNA3.1zeo-Myc vector.…”

Section: Plasmidsmentioning

confidence: 99%

Nuclear Accumulation of cRel following C-Terminal phosphorylation by TBK1/IKKε

Harris

Oliere

Sharma

et al. 2006

The Journal of Immunology

Self Cite

103

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The NF-κB transcription factors are key regulators of immunomodulatory, cell cycle, and developmental gene regulation. NF-κB activity is mainly regulated through the phosphorylation of IκB by the IκB kinase (IKK) complex IKKαβγ, leading to proteasome-mediated degradation of IκB, nuclear translocation of NF-κB dimers, DNA binding, and gene induction. Additionally, direct posttranslational modifications of NF-κB p65 and cRel subunits involving C-terminal phosphorylation has been demonstrated. The noncanonical IKK-related homologs, TNFR-associated factor family member-associated NF-κB activator (TANK)-binding kinase (TBK)1 and IKKε, are also thought to play a role in NF-κB regulation, but their functions remain unclear. TBK1 and IKKε were recently described as essential regulators of IFN gene activation through direct phosphorylation of the IFN regulatory factor-3 and -7 transcription factors. In the present study, we sought to determine whether IKKε and TBK1 could modulate cRel activity via phosphorylation. TBK1 and IKKε directly phosphorylate the C-terminal domain of cRel in vitro and in vivo and regulate nuclear accumulation of cRel, independently of the classical IκB/IKK pathway. IκBα degradation is not affected, but rather IKKε-mediated phosphorylation of cRel leads to dissociation of the IκBα-cRel complex. These results illustrate a previously unrecognized aspect of cRel regulation, controlled by direct IKKε/TBK1 phosphorylation.

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“…1B) were prepared by cloning BglII-SalI fragment (Ϫ397 to ϩ5, filled in with Klenow enzyme) from RANTES/chloramphenicol acetyltransferase reporter plasmid (25) into the NheI site (filled in with Klenow enzyme) of the pGL3-basic vector, as previously described (24). The IRF-3, IRF-7, p65/p50, and CBP expression plasmids used in cotransfection experiments have been previously described (24,26).…”

Section: Plasmid Constructions and Mutagenesismentioning

confidence: 99%

Regulation of RANTES Chemokine Gene Expression Requires Cooperativity Between NF-κB and IFN-Regulatory Factor Transcription Factors

Génin

Algarté

Roof

et al. 2000

The Journal of Immunology

Self Cite

206

208

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Virus infection of host cells activates a set of cellular genes, including cytokines, IFNs, and chemokines, involved in antiviral defense and immune activation. Previous studies demonstrated that virus-induced transcriptional activation of a member of the human CC-chemokine RANTES required activation of the latent transcription factors IFN-regulatory factor (IRF)-3 and NF-κB via posttranslational phosphorylation. In the present study, we further characterized the regulatory control of RANTES transcription during virus infection using in vivo genomic footprinting analyses. IRF-3, the related IRF-7, and NF-κB are identified as important in vivo binding factors required for the cooperative induction of RANTES transcription after virus infection. Using fibroblastic or myeloid cells, we demonstrate that the kinetics and strength of RANTES virus-induced transcription are highly dependent on the preexistence of IRFs and NF-κB. Use of dominant negative mutants of either IκB-α or IRF-3 demonstrate that disruption of either pathway dramatically abolishes the ability of the other to bind and activate RANTES expression. Furthermore, coexpression of IRF-3, IRF-7, and p65/p50 leads to synergistic activation of RANTES promoter transcription. These studies reveal a model of virus-mediated RANTES promoter activation that involves cooperative synergism between IRF-3/IRF-7 and NF-κB factors.

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Virus-Dependent Phosphorylation of the IRF-3 Transcription Factor Regulates Nuclear Translocation, Transactivation Potential, and Proteasome-Mediated Degradation

Cited by 851 publications

References 71 publications

Single-stranded RNA viruses inactivate the transcriptional activity of p53 but induce NOXA-dependent apoptosis via post-translational modifications of IRF-1, IRF-3 and CREB

Single-stranded RNA viruses inactivate the transcriptional activity of p53 but induce NOXA-dependent apoptosis via post-translational modifications of IRF-1, IRF-3 and CREB

Nuclear Accumulation of cRel following C-Terminal phosphorylation by TBK1/IKKε

Regulation of RANTES Chemokine Gene Expression Requires Cooperativity Between NF-κB and IFN-Regulatory Factor Transcription Factors

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