Kwon, H-J;
Choi, G-E;
Ryu, S;
Kwon, SJ;
Kim, SC;
Booth, C;
Nichols, KE;
(2016)
Stepwise phosphorylation of p65 promotes NF-kappa B activation and NK cell responses during target cell recognition.
Nature Communications
, 7
, Article 116. 10.1038/ncomms11686.
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Abstract
NF-κB is a key transcription factor that dictates the outcome of diverse immune responses. How NF-κB is regulated by multiple activating receptors that are engaged during natural killer (NK)-target cell contact remains undefined. Here we show that sole engagement of NKG2D, 2B4 or DNAM-1 is insufficient for NF-κB activation. Rather, cooperation between these receptors is required at the level of Vav1 for synergistic NF-κB activation. Vav1-dependent synergistic signalling requires a separate PI3K-Akt signal, primarily mediated by NKG2D or DNAM-1, for optimal p65 phosphorylation and NF-κB activation. Vav1 controls downstream p65 phosphorylation and NF-κB activation. Synergistic signalling is defective in X-linked lymphoproliferative disease (XLP1) NK cells entailing 2B4 dysfunction and required for p65 phosphorylation by PI3K-Akt signal, suggesting stepwise signalling checkpoint for NF-κB activation. Thus, our study provides a framework explaining how signals from different activating receptors are coordinated to determine specificity and magnitude of NF-κB activation and NK cell responses.
| Type: | Article |
|---|---|
| Title: | Stepwise phosphorylation of p65 promotes NF-kappa B activation and NK cell responses during target cell recognition |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/ncomms11686 |
| Publisher version: | http://dx.doi.org/10.1038/ncomms11686 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | NATURAL-KILLER-CELLS, LINKED LYMPHOPROLIFERATIVE-DISEASE, SIGNALING PATHWAYS, GENE-EXPRESSION, ENCODING GENE, EBV INFECTION, CUTTING EDGE, ADAPTER SAP, CYTOKINE, CYTOTOXICITY |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1509450 |
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