NF‐κB p52:RelB heterodimer recognizes two classes of κB sites with two distinct modes

Fusco, Amanda J.; Huang, De-Bin; Miller, D. Josh; Wang, Vivien Ya-Fan; Vu, Don; Ghosh, Gourisankar

doi:10.1038/embor.2008.227

Cited by 62 publications

(59 citation statements)

References 27 publications

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“…It suggests that nuclear accumulation of RelA, cRel and p50 in IKK2ca+ B cells can compensate for the loss of RelB:p52 activation in B cells deficient in BAFF-R signaling. Interestingly, analysis of crystal structure of RelB-containing dimers suggested that RelB may recognize a broader range of κB sequences than other dimers [93,94]. In sum, studies performed so far have not been able to reach a definite conclusion if different NFκB dimers activated by the non-canonical pathway have specific or overlapping gene activation functions.…”

Section: The Non-canonical Pathwaymentioning

confidence: 87%

A single NFκB system for both canonical and non-canonical signaling

et al. 2010

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Two distinct nuclear factor κB (NFκB) signaling pathways have been described; the canonical pathway that mediates inflammatory responses, and the non-canonical pathway that is involved in immune cell differentiation and maturation and secondary lymphoid organogenesis. The former is dependent on the IκB kinase adaptor molecule NEMO, the latter is independent of it. Here, we review the molecular mechanisms of regulation in each signaling axis and attempt to relate the apparent regulatory logic to the physiological function. Further, we review the recent evidence for extensive cross-regulation between these two signaling axes and summarize them in a wiring diagram. These observations suggest that NEMO-dependent and -independent signaling should be viewed within the context of a single NFκB signaling system, which mediates signaling from both inflammatory and organogenic stimuli in an integrated manner. As in other regulatory biological systems, a systems approach including mathematical models that include quantitative and kinetic information will be necessary to characterize the network properties that mediate physiological function, and that may break down to cause or contribute to pathology.

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Section: The Non-canonical Pathwaymentioning

confidence: 87%

A single NFκB system for both canonical and non-canonical signaling

et al. 2010

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“…By induction of both the canonical and noncanonical pathways of NF-B activation, BCL10 and CGN are positioned to influence a wide range of NF-B transcriptional effects. The p52/RelB heterodimer appears to bind to a broader spectrum of B sites than the p50/RelA heterodimer and may even bind to a modified consensus sequence (22)(23)(24). By activation of the noncanonical pathway, CGN and BCL10 may evoke responses similar to those of tumor necrosis factor-␣, as well as those elicited by inflammatory mediators such as dextran sulfate sodium that act through ROS (17).…”

Section: Discussionmentioning

confidence: 99%

B-cell CLL/Lymphoma 10 (BCL10) Is Required for NF-κB Production by Both Canonical and Noncanonical Pathways and for NF-κB-inducing Kinase (NIK) Phosphorylation

Bhattacharyya

Borthakur

Tyagi

et al. 2010

Journal of Biological Chemistry

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The importance of activation of B-cell lymphoma/CLL 10 (BCL10) 2 has been recognized previously in the mucosa-associated lymphoid tissue (MALT) lymphomas, in which translocations involving MALT1 lead to constitutive activation of BCL10 and NF-B transcription (1, 2). Other reports have defined a critical role for BCL10 in the inflammatory cascade in epithelial cells, including activation by lysophosphatidic acid (3), G-protein-coupled receptor (4), and angiotensin II (5). In this report, we demonstrate that BCL10 was required for NF-B activation by both canonical and noncanonical pathways, following stimulation by the sulfated polysaccharide carrageenan (CGN) in mouse embryonic fibroblasts and in human colonic epithelial cells. Previously, we reported that CGN significantly up-regulated transcription of BCL10 in NCM460 cells (6, 7). The sulfated polysaccharide carrageenan has been widely used for decades to induce inflammation in animal and tissue culture models. In our previous work, CGN was shown to induce an inflammatory cascade in human colonic epithelial cells by two distinct mechanisms: an immune-mediated mechanism involving TLR4 (toll-like receptor 4), IRAK (IL-1␤ receptor activating kinase), BCL10, phospho-IB␣ (inhibitor of B), NF-B (nuclear factor B), and IL-8 (interleukin-8); and a reactive oxygen species (ROS)-mediated mechanism involving phospho-Hsp27, IB kinase (IKK)-␤, phospho-IB␣, BCL10, NF-B, and . Carrageenan activation of these pathways was attributable to its distinctive chemical structure, including its resemblance to the naturally occurring glycosaminoglycans, its highly sulfated galactose residues, and its unusual ␣-Gal(133)Gal bond that is a known immune epitope (10, 11). Because CGN is a commonly used food additive in the Western diet, these pathways may induce inflammation and disease in the human colon and implicate a role for BCL10 in human disease, in addition to the MALT lymphomas.To further define the BCL10-mediated activation of NF-B and the interactions between the ROS and TLR4-BCL10 pathways, the requirements for different components of the IKK signaling complex and the responses of different members of the NF-B family were investigated. The IKK signaling complex, including the catalytic components IKK␣ and IKK␤ and the regulatory component IKK␥, also known as NEMO (NF-B essential modifying factor), integrates upstream signals and leads to the phosphorylation of IB␣. Subsequently, phospho-IB␣ is ubiquitinated, and the localization signal for NF-B nuclear translocation is exposed. These events represent critical signals in the progression of the inflammatory cascade from * This work was supported in part by the Department of Veterans Affairs (to J. K. T.) and by NIDDK, National Institutes of Health Grants DK68324 and DK54016 (to P. K. D.

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“…RelB also contains a unique segment at its N terminus, which is referred to as the leucine zipper domain. We previously reported that RelB and p100 bind to one another through a complex interface that involves interactions between multiple domains on both subunits (5). We reasoned that a more complicated mode of interaction between RelB and p100 could play a role in regulating the stability and processing of p100.…”

Section: Resultsmentioning

confidence: 99%

“…RelB confers transcriptional activity by associating primarily with two other NF-kB family members, p50 and p52 (3)(4)(5). RelB also associates with RelA, but the resulting RelA:RelB heterodimer is incapable of binding to DNA (6).…”

Section: Introductionmentioning

confidence: 99%