Regulation of nuclear factor kappa B subunit c-Rel through phosphorylation by two IKK-related kinases, IKK epsilon and TBK-1
Bibliographic record
Abstract
The nuclear factor kappaB (NF-kappaB) transcription factors are key regulators of immunomodulatory genes regulation. NF-kappaB activity is regulated through the phosphorylation of inhibitory proteins (IkappaBs) by the IkappaB kinase (IKK) complex (IKK alpha/beta/gamma), leading to IkappaB degradation and NF-kappaB translocation to the nucleus where they promote transcription of immunoregulatory genes. Moreover, cRel and p65 activities are also regulated by direct phosphorylation of their transactivation domain. Recently, two IKK non-canonical homologues, IKKepsilon and TBK-1 (TANK binding kinase-1) have been identified with functions distinct from the classical IKKalpha/IKKbeta. TBK-1/IKKepsilon trigger antiviral immunity through direct phosphorylation of the IRF3/IRF7 transcription factors, which are key regulators of the interferon response. Since IKKepsilon modulates the activity of IRF3/IRF7, it is of interest to assess whether IKKepsilon/TBK-1 also regulates the transactivation activity of NF-kappaB. Our hypothesis was that IKKepsilon/TBK-1 modulates the activity of cRel by direct phosphorylation of its transactivation domain (TD). In this study, we demonstrate that IKKepsilon and TBK-1 directly phosphorylate cRel in vitro and in vivo. Two of the three consensus sequences recognized by IKKepsilon/TBK-1 in the cRel TD are directly phosphorylated by IKKepsilon. cRel was translocated to the nucleus in cells expressing wild type versus kinase dead variant. The expression of IKKepsilon increases c-Rel transactivation in reporter gene assays. Serine to alanine mutation was further used to characterize the function of this phosphorylation at the level of nuclear translocation and transactivation potential using immunofluorescence and reporter gene assay. Furthermore, co-expression studies revealed that IKKepsilon and not the kinase dead variant is responsible for cRel degradation in a dose-dependent manner and this effect is partially revert
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".