The Transcriptional Specificity of NF-κB Dimers Is Coded within the κB DNA Response Elements

Wang, Vivien Ya-Fan; Huang, Wendy; Asagiri, Masataka; Spann, Nathanael J.; Hoffmann, Alexander; Glass, Christopher K.; Ghosh, Gourisankar

doi:10.1016/j.celrep.2012.08.042

Cited by 90 publications

(109 citation statements)

References 47 publications

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“…Because of the extenuated expression of IL-10 in vivo and in vitro, we analyzed the influence of IkB NS in IL-10 expression by ChIP, which revealed binding of IkB NS to the IL-10 gene locus. Previous studies identified the binding of NF-kB to the IL-10 gene locus (42,43). Thus, we suggest that IkB NS binding to the IL-10 gene locus is mediated by p50 and/or c-Rel, because IkB NS itself has no DNA-binding domain.…”

Section: Discussionmentioning

confidence: 79%

IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

Annemann

Wang

Plaza-Sirvent

et al. 2015

The Journal of Immunology

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IL-17–producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-κB has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-κB, IκBNS, in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IκBNS is crucial for murine Th17 cell generation. IκBNS is highly expressed in Th17 cells; in the absence of IκBNS, the frequencies of IL-17A–producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IκBNS−/− Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL-10, MIP-1α, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IκBNS−/− mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation-associated pathology. We identified IκBNS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections.

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Section: Discussionmentioning

confidence: 79%

IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

Annemann

Wang

Plaza-Sirvent

et al. 2015

The Journal of Immunology

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“…The transcriptional specificity of NF-B dimers is generally thought to be coded within the B site sequences (27,49). Indeed, in the case of the Lcn2 promoter, its B site effectively interacts with the NF-B p50 homodimer but not with the p52 homodimer (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the secondarily induced genes Lcn2 (encoding the antibacterial protein lipocalin-2) and Ptx3 (encoding the antibacterial protein pentraxin 3) are activated by the nuclear IB protein IB (20 -24), which serves as a key regulator in the immune system (16,18,25,26). On the other hand, Bcl-3 participates in transcriptional control of the chemokine-encoding genes Ccl2 for monocyte chemoattractant protein-1 (MCP-1) and Cxcl10 for interferon-␥-induced protein 10 (IP-10) (27), and IB NS regulates transcription of Il6 (encoding the pro-inflammatory cytokine interleukin-6) and Il12b (encoding interleukin-12 subunit p40) (28,29).…”

mentioning

confidence: 99%

The Nuclear Protein IκBζ Forms a Transcriptionally Active Complex with Nuclear Factor-κB (NF-κB) p50 and the Lcn2 Promoter via the N- and C-terminal Ankyrin Repeat Motifs

Kohda

Yamazaki

Sumimoto

2016

Journal of Biological Chemistry

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The nuclear protein IB, comprising the N-terminal transactivation domain and the C-terminal ankyrin repeat (ANK) domain composed of seven ANK motifs, activates transcription of a subset of nuclear factor-B (NF-B)-dependent innate immune genes such as Lcn2 encoding the antibacterial protein lipocalin-2. Lcn2 activation requires formation of a complex containing IB and NF-B p50, a transcription factor that harbors the DNA-binding Rel homology region but lacks a transactivation domain, on the promoter with the canonical NF-Bbinding site (B site) and its downstream cytosine-rich element. Here we show that IB productively interacts with p50 via Asp-451 in the N terminus of ANK1, a residue that is evolutionarily conserved among IB and the related nuclear IB proteins Bcl-3 and IB NS . Threonine substitution for Asp-451 abrogates direct association with the B-site-binding protein p50, complex formation with the Lcn2 promoter DNA, and activation of Lcn2 transcription. The basic residues Lys-717 and Lys-719 in the C-terminal region of ANK7 contribute to IB binding to the Lcn2 promoter, probably via interaction with the cytosinerich element required for Lcn2 activation; glutamate substitution for both lysines results in a loss of transcriptionally active complex formation without affecting direct contact of IB with p50. Both termini of the ANK domain in Bcl-3 and IB NS function in a manner similar to that of IB to interact with promoter DNA, indicating a common mechanism in which the nuclear IBs form a regulatory complex with NF-B and promoter DNA via the invariant aspartate in ANK1 and the conserved basic residues in ANK7. Nuclear factor-B (NF-B)2 plays central roles in host defense and inflammation as a homo-or heterodimer of NF-B/Rel family proteins by controlling the expression of genes for pro-inflammatory cytokines, chemokines, and antibacterial proteins (1-4). The mammalian NF-B family is composed of five structurally related polypeptides: p50, p52, p105 (the precursor of p50), p100 (the precursor of p52), p65 (also known as RelA), RelB, and c-Rel. They share the Rel homology region, which mediates dimerization, nuclear translocation, binding to specific DNA sequences known as NF-B-binding elements (B sites), and association with one of the IB family proteins (1-4). Among the members of the family, p65, RelB, and c-Rel have an ability to activate transcription by themselves via the C-terminal trans-activation domain, which is absent in the smaller p50 and p52 proteins. In resting cells, NF-B dimers are retained in the cytoplasm by associating with a member of the prototypical/cytoplasmic IB proteins including IB␣, IB␤, and IB⑀ (1-4). Cell activation with appropriate stimuli such as bacterial LPS leads to phosphorylation-induced degradation of cytoplasmic IBs and resultant liberation of NF-B dimers (1, 5, 6). The released NF-B dimers subsequently translocate to the nucleus and thus induce the expression of primary response genes via binding to B sites on their promoter/enhancer regions (1-4).The primarily induced gen...

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“…The silencing of B-cell lymphoma 3-encoded protein, a coactivator of NF-kB, inhibited Hv1 channel expression in LPSstimulated mouse macrophages (Wang et al, 2012a), suggesting a role of the NF-kB/ B-cell lymphoma 3-encoded protein complex in Hv1 transcriptional regulation. The expression of NOX subunit gp91 phox is also controlled by NF-kB in monocytic cell lines, demonstrating an upregulation upon LPS stimulation that was inhibited in cells constitutively expressing nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (Anrather et al, 2006).…”

Section: Role Of Proton Channel Hv1 In Immune Cellsmentioning

confidence: 99%

Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives

et al. 2016

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The pharmacological modulation of the immunosuppressive tumor microenvironment has emerged as a relevant component for cancer therapy. Several approaches aiming to deplete innate and adaptive suppressive populations, to circumvent the impairment in antigen presentation, and to ultimately increase the frequency of activated tumor-specific T cells are currently being explored. In this review, we address the potentiality of targeting the voltage-gated proton channel, Hv1, as a novel strategy to modulate the tumor microenvironment. The function of Hv1 in immune cells such as macrophages, neutrophils, dendritic cells, and T cells has been associated with the maintenance of NADPH oxidase activity and the generation of reactive oxygen species, which are required for the host defense against pathogens. We discuss evidence suggesting that the Hv1 proton channel could also be important for the function of these cells within the tumor microenvironment. Furthermore, as summarized here, tumor cells express Hv1 as a primary mechanism to extrude the increased amount of protons generated metabolically, thus maintaining physiologic values for the intracellular pH. Therefore, because this channel might be relevant for both tumor cells and immune cells supporting tumor growth, the pharmacological inhibition of Hv1 could be an innovative approach for cancer therapy. With that focus, we analyzed the available compounds that inhibit Hv1, highlighted the need to develop better drugs suitable for patients, and commented on the future perspectives of targeting Hv1 in the context of cancer therapy.

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The Transcriptional Specificity of NF-κB Dimers Is Coded within the κB DNA Response Elements

Cited by 90 publications

References 47 publications

IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

The Nuclear Protein IκBζ Forms a Transcriptionally Active Complex with Nuclear Factor-κB (NF-κB) p50 and the Lcn2 Promoter via the N- and C-terminal Ankyrin Repeat Motifs

Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives

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