RelB Forms Transcriptionally Inactive Complexes with RelA/p65

Marienfeld, Ralf; May, Michael J.; Berberich, Ingolf; Serfling, Edgar; Ghosh, Sankar; Neumann, Manfred

doi:10.1074/jbc.m301945200

Cited by 132 publications

(121 citation statements)

References 32 publications

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“…The 3xB firefly luciferase reporter plasmid and the Renilla luciferase reporter plasmid were described previously (27). The GST-NEMO expression vectors were generated by inserting the wild type or the mutated NEMO cDNA in-frame into the EcoRI and XhoI sites of the pGex 4T1 vector.…”

Section: Methodsmentioning

confidence: 99%

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Phosphorylation of Serine 68 in the IκB Kinase (IKK)-binding Domain of NEMO Interferes with the Structure of the IKK Complex and Tumor Necrosis Factor-α-induced NF-κB Activity

Palkowitsch

Leidner

Ghosh

et al. 2008

Journal of Biological Chemistry

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The transcription factor NF-B plays a crucial role in the initiation of innate and adaptive immune responses, in inflammation and tumorigenesis (1-3). In its inactive state NF-B is bound to small cytoplasmic proteins, the IB proteins. Stimulation with a wide variety of agonists, for example pro-inflammatory cytokines like TNF-␣, 2 bacterial components like lipopolysaccharide or by antigen receptors, funnels in the activation of a multisubunit IB-kinase complex, which phosphorylates the IB proteins at two specific serine residues. This phosphorylation marks the IB proteins for proteasomal degradation setting NF-B free, which then translocates into the nucleus and supports the expression of various pro-inflammatory or anti-apoptotic gene products. The IB kinase (IKK) complex is composed of two catalytically active subunits, termed IKK␣ (IKK1) and IKK␤ (IKK2), as well as NEMO/IKK␥, a subunit with regulatory and adaptor functions (4, 5). Analysis of mice deficient for either IKK␣ or IKK␤ suggested that the IKK␤ subunit is the major IKK regulating the canonical NF-B pathway, and the IKK␣ subunit is crucial for a second, alternative NF-B pathway leading to the activation of RelB-p52 heterodimers (6, 7). In contrast to the canonical NF-B pathway, which depends on the presence of NEMO, the alternative pathway is NEMO-independent but requires the protein kinase NIK. However, recent data suggest that, instead of a clear assignment of IKK␣ and IKK␤ to the alternative and the canonical NF-B pathway, respectively, both kinases contribute to the activation of NF-B by the canonical pathway with only gradual differences (8,9). Although a precise model regarding the molecular mechanism underlying IKK activation is still missing, it became clear that various post-translational modifications at the different IKK subunits are involved in this process. Besides the phosphorylation of IKK␣ and IKK␤ at two serine residues in their T-loop, the ubiquitination and occasionally the phosphorylation at a specific serine residue of NEMO seem to be required (10 -12). This serine residue at position 85 of NEMO has been identified as a protein kinase C␣, and more recently as an ATM target-site crucial for the IKK activation induced by genotoxic stress (12, 13). In addition, overexpression of the TNF-␣-receptor I or the human T-cell lymphotrophic virus I Tax protein induces the IKK␤-mediated NEMO phosphorylation at several

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Section: Methodsmentioning

confidence: 99%

“…Immunoprecipitation, GST Pulldown, and ImmunoblottingThe immunoprecipitation and immunoblotting procedures were performed as described previously (27). In brief, 0.5-1 mg of protein extracts were mixed with 25 l of bovine serum albumin-blocked FLAG-antibody (M2, Sigma) linked to agarose beads.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of Serine 68 in the IκB Kinase (IKK)-binding Domain of NEMO Interferes with the Structure of the IKK Complex and Tumor Necrosis Factor-α-induced NF-κB Activity

Palkowitsch

Leidner

Ghosh

et al. 2008

Journal of Biological Chemistry

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“…In addition, there is in vivo and in vitro evidence that the individual Rel proteins have distinct biological activities, but the precise physiological role of each protein is not completely understood (Gerondakis et al, 1999;Vainer et al, 2008). In particular, transcription repression functions have been attributed to homodimers of p50 as well as to NF-κB heterodimers of RelB (Baer et al, 1998;Xia et al, 1999;Marienfeld et al, 2003). The repressive properties may serve to fine tune immune and inflammatory responses regulated by NF-κB.…”

Section: Nf-kb1 (P50) Protects From Chronic Liver Injurymentioning

confidence: 99%

NF‐κB in liver diseases: a target for drug therapy

Muriel

2008

J of Applied Toxicology

144

106

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There are five nuclear factor-kB (NF-kB) transcription factors with important roles in innate immunity, liver inflammation, fibrosis and apoptosis prevention. Several inhibitors of NF-kB, like caffeic acid, captopril, curcumin, pyrrolidine dithiocarbamate, resveratrol, silymarin and thalidomide, have demonstrated antinecrotic, anticholestatic, antifibrotic and anticancer activities in the liver. A link between inflammation and hepatocellular carcinoma through the NF-kB pathway has been observed, providing ample experimental support for the tumor-promoting function of NF-kB in various models of cancer. NF-kB has been associated with the induction of proinflammatory gene expression and has attracted interest as a target for the treatment of inflammatory disease. However, despite much attention being focused on the deleterious effects of NF-kB, activation of this factor during the resolution of inflammation is associated with the production of antiinflammatory molecules like interleukin (IL)-10 and the onset of apoptosis. This suggests that NF-kB has an antiinflammatory role in vivo involving the regulation of the resolution of inflammation. Also, NF-kB promotes liver regeneration by upregulating IL-6 and other molecules like hepatocyte growth factor. It has been postulated that the beneficial properties of NF-kB are due to p50 homodimers, whose activation prevents cholestatic and chronic liver injury. More basic understanding on the function of the diverse NF-kB factors is urgently needed in different physiological and pathological conditions, because depending on the subunit composition of the dimmer, the disease and the stage of the illness, inhibition of the factor may result in a beneficial or in a deleterious response. Copyright © 2008 John Wiley & Sons, Ltd.There are five nuclear factor-kB (NF-kB) transcription factors with important roles in innate immunity, liver inflammation, fibrosis, and apoptosis prevention. Several inhibitors of NF-kB have demonstrated antinecrotic, anticholestatic, antifibrotic and anticancer activities in the

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“…The stimulus-induced RelB degradation is an alternative IkB-independent mechanism of NF-kB regulation known to occur not only in T cells but also in other lymphoid and non-lymphoid cells (Marienfeld et al, 2001(Marienfeld et al, , 2003. RelB is one of the five mammalian Rel proteins of which the NF-kB dimer is composed.…”

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confidence: 99%

Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation

et al. 2011

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The immediate early transcription factor nuclear factor (IjBs) kappa B (NF-jB) is crucially involved in the regulation of numerous physiological or pathophysiological processes such as inflammation and tumourigenesis. Therefore, the control of NF-jB activity, which is mainly regulated by signal-induced degradation of cytoplasmic inhibitors of NF-jB (IjBs), is of high relevance. One known alternative pathway of NF-jB regulation is the stimulus-induced proteasomal degradation of RelB, a component of the NF-jB dimer. Here, we identified the serine/threonine protein kinase glycogen synthase kinase-3b (GSK-3b) as a critical signalling component leading to RelB degradation. In Jurkat leukaemic T cells as well as in primary human T cells, tetradecanoylphorbolacetate/ionomycinand CD3/CD28-induced RelB degradation were impaired by a GSK-3b-specific pharmacological inhibitor, an ectopically expressed dominant-negative GSK-3b mutant and by small-interfering RNA-mediated silencing of GSK-3b expression. Furthermore, a physical interaction between RelB and GSK-3b was shown by co-immunoprecipitation, which was already notable in unstimulated cells. Most importantly, as demonstrated by in vitro kinase assays, human RelB is inducibly phosphorylated by GSK-3b, indicating a direct substrate-enzyme relationship. The serine residue 552 is a target of GSK-3b-mediated phosphorylation in vitro and in vivo. We conclude that GSK-3b is a crucial regulator of RelB degradation, stressing the relevant linkage between the NF-jB system and GSK-3b.

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RelB Forms Transcriptionally Inactive Complexes with RelA/p65

Cited by 132 publications

References 32 publications

Phosphorylation of Serine 68 in the IκB Kinase (IKK)-binding Domain of NEMO Interferes with the Structure of the IKK Complex and Tumor Necrosis Factor-α-induced NF-κB Activity

Phosphorylation of Serine 68 in the IκB Kinase (IKK)-binding Domain of NEMO Interferes with the Structure of the IKK Complex and Tumor Necrosis Factor-α-induced NF-κB Activity

NF‐κB in liver diseases: a target for drug therapy

Glycogen synthase kinase-3β is a crucial mediator of signal-induced RelB degradation

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