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Nat. Commun., Published 25 May 2016, 7, Article number: 11686 | doi:10.1038/ncomms11686 Stepwise phosphorylation of p65 promotes NF-κB activation and NK cell responses during target cell recognition

Abstract

Hyung-Joon Kwon¹, Go-Eun Choi^1,2, Sangryeol Ryu³, Soon Jae Kwon¹, Sun Chang Kim⁴, Claire Booth⁵, Kim E. Nichols⁶ & Hun Sik Kim^1,7,8

¹ Department of Biomedical Sciences, University of Ulsan College of Medicine, 86 Asanbyeongwon-Gil, Seoul 138-735, Korea. ² Institute of Convergence Bio-Health, Dong-A University, Busan, Korea. ³ Department of Food and Animal Biotechnology, Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Korea. ⁴ Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea. ⁵ Molecular Immunology Unit, Institute of Child Health, University College London, London WC1N 1EH, UK.⁶ Department of Oncology, Division of Cancer Predisposition, St Jude Children’s Research Hospital, Memphis, Tennessee 38105-3678, USA. ⁷ Department of Microbiology, University of Ulsan College of Medicine, Seoul 138-735, Korea. ⁸ Cellular Dysfunction Research Center, University of Ulsan College of Medicine, Seoul 138-735, Korea.

Correspondence to : Hun Sik Kim

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.

논문정보

형식Research article
게재일2016년 05월 (BRIC 등록일 2016-05-30)
연구진국내(교신)+국외 연구진
분야 의약학 > 면역의학

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