Stepwise phosphorylation of p65 promotes NF-κB activation and NK cell responses during target cell recognition

Hyung-Joon Kwon, Go-Eun Choi, Sangryeol Ryu, Soon Jae Kwon, Sun Chang Kim, Claire Booth, Kim E. Nichols and Hun Sik Kim ()
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Hyung-Joon Kwon: University of Ulsan College of Medicine, 86 Asanbyeongwon-Gil
Go-Eun Choi: University of Ulsan College of Medicine, 86 Asanbyeongwon-Gil
Sangryeol Ryu: Research Institute for Agriculture and Life Sciences, Seoul National University
Soon Jae Kwon: University of Ulsan College of Medicine, 86 Asanbyeongwon-Gil
Sun Chang Kim: Korea Advanced Institute of Science and Technology
Claire Booth: Molecular Immunology Unit, Institute of Child Health, University College London
Kim E. Nichols: St Jude Children’s Research Hospital
Hun Sik Kim: University of Ulsan College of Medicine, 86 Asanbyeongwon-Gil

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11686

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