Virus Infection Induces the Assembly of Coordinately Activated Transcription Factors on the IFN-β Enhancer In Vivo

Wathelet, Marc; Lin, Charles; Parekh, Bhavin S.; Ronco, Lucienne; Howley, Peter M.; Maniatis, Tom

doi:10.1016/s1097-2765(00)80051-9

Cited by 677 publications

(743 citation statements)

References 34 publications

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“…Transcriptional regulation is complex, requiring promoter access via deacetylation of histones and coordinated assembly of several transcription factors including IRF3, IRF7, CEBP/p300, AP-1 (ATF-2/c-Jun), and NF-jB [42][43][44][45]. We have not found any XBP-1 binding sites in the IFN-b gene promoter region using TFSEARCH and the TRANSFAC database, suggesting that XBP-1 is unlikely to directly activate IFN-b gene transcription.…”

Section: Discussionmentioning

confidence: 87%

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

et al. 2008

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Type I IFN are strongly induced upon engagement of certain pattern recognition receptors by microbial products, and play key roles in regulating innate and adaptive immunity. It has become apparent that the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), in addition to restoring ER homeostasis, also influences the expression of certain inflammatory cytokines. However, the extent to which UPR signaling regulates type I IFN remains unclear. Here we show that cells undergoing a UPR respond to TLR4 and TLR3 ligands, and intracellular dsRNA, with log-fold greater IFN-b induction. This synergy is not dependent on autocrine type I IFN signaling, but unexpectedly requires the UPR transcription factor X-box binding protein 1 (XBP-1). Synergistic IFN-b induction also occurs in HLA-B27/human b 2 m-transgenic rat macrophages exhibiting a UPR as a consequence of HLA-B27 up-regulation, where it correlates with activation of XBP-1 splicing. Together these findings indicate that the cellular response to endogenous 'danger' that disrupts ER homeostasis is coupled to IFN-b induction by XBP-1, which has implications for the immune response and the pathogenesis of diseases involving the UPR.Key words: HLA-B27 Á Interferons Á Protein misfolding Á Unfolded protein response IntroductionInitially identified as antiviral cytokines, type I IFN (IFN-a/b) are now recognized to have diverse immunoregulatory effects activating macrophages and NK cells, promoting T cell survival and dendritic cell (DC) maturation, and increasing the production of Th1-polarizing cytokines to mediate innate and adaptive immune responses [1]. Type I IFN also exert biological effects at low and even constitutive levels of expression [2]. For example, weak IFN-b-mediated signaling augments IFN-a/b induction in response to LPS through positive feedback involving autocrine/ paracrine up-regulation of IFN regulatory factor (IRF)7. In addition, low levels of IFN-a/b prime cells to respond to IFN-c and IL-6 by providing a phosphorylated type I IFN receptor 'niche' for commonly used signaling molecules in proximity to other cytokine receptor complexes [3,4]. Mice deficient in IFN-b are more susceptible to viral infection, have lower numbers of macrophages and mature B cells, and exhibit reduced bone mass [5], as IFN-b is a positive regulator of bone formation through inhibition of osteoclast differentiation [6]. Thus, even constitutive levels of this cytokine are important in osteo-immune homeostasis.IFN-b is produced by most cell types upon viral infection, and in large amounts by macrophages and DC, following engagement of pattern recognition receptors (PRR) by conserved molecular structures referred to as pathogen-associated molecular patterns [7, 8]. PRR that mediate IFN-b induction include cell surface TLR4 and endosomal TLR3 for LPS and dsRNA, respectively [9]. In both instances increased IFN-b gene transcription occurs via TLR/IL-1R domain-containing adapter inducing IFN-b (TRIF)-dependent IRF3 and NF-jB activation. PRR in the retinoic ...

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Section: Discussionmentioning

confidence: 87%

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

et al. 2008

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“…Following virus infection, IRF-3, NF-B, and the activating transcription factor-2/c-Jun complex are activated by posttranslational phosphorylation and cooperate to form a transcriptionally active enhanceosome complex, at the promoter of the immediate early IFN-␤ gene, in association with the CBP/p300 coactivator and the chromatin-associated HMG proteins (35,36). Secreted IFN produced as a consequence of this protein synthesis-independent mechanism acts through an autocrine or paracrine loop to activate the Jak/STAT pathway.…”

Section: Formation Of An Enhanceosome On the Rantes Promotermentioning

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

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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“…Furthermore, Drosphila or yeast cells were analysed in most cases (Orlando and Paro, 1993;Walter and Biggin, 1996;Rundlett et al, 1998), which have much smaller genome complexities than the mammals. More recently, the above approach has been used for the study of Oct-4 factor binding in the Osteopontin enhancer (Botquin et al, 1998), and for the demonstration of association of transcriptional activators with virus-induced promoters in vivo (Wathelet et al, 1998). The reciprocal binding patterns of the AP1 and NF-E2 factors in the c-jun promoter and the b-globin-LCR in K562 cells (Figures 2 and 3) have clearly demonstrated the feasibility of the strategy outlined in Figure 2A for determining the identity of nuclear factor(s) bound in vivo at speci®c motif(s) to which a family of related DNA-binding factors could recognize and interact with.…”

Section: C-jun Promoter Is Bound With Ap1 But Not Nf-e2 In K562 Cellsmentioning

confidence: 99%

Distinction between AP1 and NF-E2 factor-binding at specific chromatin regions in mammalian cells

1999

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Speci®c nuclear factor-DNA complexes formed within the promoters and enhancers are essential for transcriptional regulation. For eukaryotic systems, however, some DNA motif(s) are capable of binding to a family of related factors, thus making it di cult to identify the factor actually binding on the chromatic DNA in vivo and modulating the local transcription processes. To resolve this matter, we have re®ned a chromatin immunoprecipitation assay. Using the assay, we could directly link the regulatory functions of two members of the AP1/NF-E2 transcription factor family and their stable binding in vivo within distinct chromatin regions. The study demonstrated the feasibility of a general scheme in the determination of the identity of speci®c factor(s), among a group of family members, bound at unique sequence(s) in living mammalian cells.

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Virus Infection Induces the Assembly of Coordinately Activated Transcription Factors on the IFN-β Enhancer In Vivo

Cited by 677 publications

References 34 publications

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

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

Distinction between AP1 and NF-E2 factor-binding at specific chromatin regions in mammalian cells

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