Stimulus-specific Induction of a Novel Nuclear Factor-κB Regulator, IκB-ζ, via Toll/Interleukin-1 Receptor Is Mediated by mRNA Stabilization

Yamazaki, Soh; Muta, Tsuyoshi; Matsuo, Susumu; Takeshige, Koichiro

doi:10.1074/jbc.m409983200

Cited by 124 publications

(148 citation statements)

References 54 publications

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“…This protein, designated IκB-ζ , is barely detectable in resting cells, but is induced not only by LPS, but also by other microbial components that stimulate TLRs such as peptidoglycan, bacterial lipopeptide and CpG DNA [17][18][19]. The induction is also observed upon stimulation with IL (interleukin)-1β, but not by another pro-inflammatory cytokine, TNF (tumour necrosis factor)-α [17,20]. The protein IκB-ζ was also identified by other groups as MAIL (molecule possessing ankyrin repeats induced by LPS) [21] or INAP (IL-1-inducible nuclear ankyrin repeat protein) [22].…”

Section: Introductionmentioning

confidence: 80%

“…We designated the longer form IκB-ζ (L) and the shorter form IκB-ζ (S), which lacks the N-terminal 99 amino acids of IκB-ζ (L). Both forms of IκB-ζ are induced upon stimulation, and IκB-ζ (L) is the predominant form in macrophages stimulated by LPS [20]. In contrast with the typical cytosolic and constitutively expressed IκB proteins, IκB-ζ is localized in the nucleus, where it preferentially binds, via the C-terminal ankyrin repeats, to the NF-κB p50 subunit rather than to the p65 subunit [17].…”

Section: Introductionmentioning

confidence: 99%

“…The protein IκB-ζ was also identified by other groups as MAIL (molecule possessing ankyrin repeats induced by LPS) [21] or INAP (IL-1-inducible nuclear ankyrin repeat protein) [22]. In a recent study, we showed that the stimulus specificity of IκB-ζ induction is determined at the post-transcriptional level, but not at the transcriptional level, on the basis of the finding that the stability of IκB-ζ mRNA is specifically upregulated by stimulation with LPS or IL-1β, but not with TNF-α [20]. At least two major IκB-ζ variants are generated by alternative splicing [17,21].…”

Section: Introductionmentioning

confidence: 99%

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Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activation

Matsuo

Yamazaki

Takeshige

et al. 2007

Biochemical Journal

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IκB-ζ [inhibitor of NF-κB (nuclear factor κB) ζ ] is a nuclear protein that is induced upon stimulation of TLRs (Toll-like receptors) and IL (interleukin)-1 receptor. IκB-ζ harbours Cterminal ankyrin repeats that interact with NF-κB. Our recent studies have shown that, upon stimulation, IκB-ζ is essential for the induction of a subset of inflammatory genes, represented by IL-6, whereas it inhibits the expression of TNF (tumour necrosis factor)-α. In the present study, we investigated mechanisms that determine the different functions of IκB-ζ . We found that coexpression of IκB-ζ and the NF-κB subunits synergistically activates transcription of the hBD-2 (human β-defensin 2) and NGAL (neutrophil gelatinase-associated lipocalin) genes, whereas it inhibits transcription of E-selectin. Reporter analyses indicated that, in addition to an NF-κB-binding site, a flanking C/EBP (CCAAT/enhancer-binding protein)-binding site in the promoters is essential for the IκB-ζ -mediated transcriptional activation. Using an artificial promoter consisting of the NF-κB-and C/EBP-binding sites, transcriptional activation was observed upon co-transfection with IκB-ζ and NF-κB, indicating that these sequences are minimal elements that confer the IκB-ζ -mediated transcriptional activation. Chromatin immunoprecipitation assays and knockdown experiments showed that both IκB-ζ and the NF-κB subunits were recruited to the NGAL promoter and were essential for the transcriptional activation of the hBD-2 and NGAL promoters on stimulation with IL-1β. The activation of the NGAL promoter by transfection of IκB-ζ and NF-κB was suppressed in C/EBPβ-depleted cells. Thus IκB-ζ acts as an essential transcriptional activator by forming a complex with NF-κB on promoters harbouring the NF-κB-and C/EBP-binding sites, upon stimulation of TLRs or IL-1 receptor.Key words: CCAAT/enhancer-binding protein (C/EBP), inflammation, inhibitor of nuclear factor κB ζ (IκB-ζ ), innate immunity, nuclear factor κB (NF-κB), transcription.

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Section: Introductionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activation

Matsuo

Yamazaki

Takeshige

et al. 2007

Biochemical Journal

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“…Among the possible explanations are epigenetic alterations of the gene locus in HepG2 cells or mRNA instability. The induction of IkB-z, a close relative of BCL3, requires activation by NF-kB and stimulus-specific stabilization of its mRNA (Yamazaki et al, 2005). Assuming a similar mechanism for BCL3, both NF-kB and Stat3 can activate transcription, but only NF-kB additionally stabilizes BCL3 mRNA.…”

Section: Discussionmentioning

confidence: 99%

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Brocke-Heidrich

Cvijic

et al. 2006

Oncogene

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BCL3 is a proto-oncogene affected by chromosomal translocations in some patients with chronic lymphocytic leukemia. It is an IjB family protein that is involved in transcriptional regulation of a number of NF-jB target genes. In this study, interleukin (IL)-6-induced BCL3 expression and its effect on survival of multiple myeloma (MM) cells were examined. We demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence analysis of the BCL3 gene locus revealed four potential signal transducer and activator of transcription (Stat) binding sites within two conserved intronic enhancers regions: one located within enhancer HS3 and three within HS4. Chromatin immunoprecipitation experiments showed increased Stat3 binding to both enhancers upon IL-6 stimulation. Silencing Stat3 expression by small interfering RNA (siRNA) abrogated BCL3 expression by IL-6. Using reporter gene assays, we demonstrate that BCL3 transcription depends on HS4. Mutation of the Stat motifs within HS4 abolished IL-6-dependent BCL3 induction. Furthermore, BCL3 transcription was inhibited by its own gene product. This repressive feedback is mediated by NF-jB sites within the promoter and HS3. Finally, we show that overexpression of BCL3 increases apoptosis, whereas BCL3-specific siRNA does not affect the viability of INA-6 cells suggesting that BCL3 is not essential for the survival of these cells.

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“…Conversely, human IkBz expression is strongly induced by TNFa (Totzke et al, 2006). Stimulation with TLR ligands results in the production of three different alternative splicing variants of IkBz: L, S, and D. IkBz (L) is predominantly expressed in response to LPS stimulation (Kitamura et al, 2002;Yamazaki et al, 2005), while expression of IkBz (S) has been observed at the mRNA and protein levels in minor species . Although IkBz (D) mRNA has been detected in macrophages, the corresponding protein has not been found.…”

Section: Introductionmentioning

confidence: 99%

Molecular modeling‐based evaluation of dual function of IκBζ ankyrin repeat domain in toll‐like receptor signaling

Manavalan

Govindaraj

Lee

et al. 2010

J of Molecular Recognition

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IkBz (inhibitor of NF-kB (nuclear factor kB) z) is a nuclear protein induced upon stimulation of toll-like receptors (TLRs) and interleukin-1 receptor. Induced IkBz, especially its C-terminal ankyrin repeat domain (ARD), interacts with NF-kB in the nucleus, where it regulates the transcriptional activity of target genes. Recent studies have shown that human ARD of IkBz binds with p50/p65 heterodimer and inhibits the transcription of NF-kB regulated genes, whereas mouse ARD of IkBz binds with p50/p50 homodimer and exhibits transcriptional activation activity. Since human and mouse IkBz ARD are identical, it is unclear how IkBz can be a positive and negative regulator of NF-kB-mediated transcription. Therefore, we generated a structural model of IkBz ARD and constructed a detailed molecular dynamics (MD) simulation of IkBz in explicit solvent to investigate ARD flexibility. In addition, we used molecular docking to screen for potential sites of interaction between IkBz and the p50/p65 heterodimer and IkBz and the p50/p50 homodimer. The docking experiments revealed that the binding of IkBz ankyrin repeats with the p50/p65 N-terminal DNA binding domain prevents NF-kB-mediated transcriptional activation. Furthermore, the IkBz-p50 homodimer complex, which lacks Pro, Glu (and Asp), Ser and Thr (PEST motif), facilitated gene expression. These two different binding schemes of IkBz may be responsible for its opposite function, which is consistent with the currently available biochemical data. Moreover, our data implicate structurally highly flexible ARD residues as the prime contributors to this dual function.

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Stimulus-specific Induction of a Novel Nuclear Factor-κB Regulator, IκB-ζ, via Toll/Interleukin-1 Receptor Is Mediated by mRNA Stabilization

Cited by 124 publications

References 54 publications

Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activation

Crucial roles of binding sites for NF-κB and C/EBPs in IκB-ζ-mediated transcriptional activation

BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Molecular modeling‐based evaluation of dual function of IκBζ ankyrin repeat domain in toll‐like receptor signaling

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