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

Nat Commun. 2016 May 25;7:11686. doi: 10.1038/ncomms11686.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Differentiation, T-Lymphocyte / metabolism*
  • Humans
  • Killer Cells, Natural / metabolism*
  • Lymphoproliferative Disorders / metabolism
  • NF-kappa B / metabolism*
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism*
  • Proto-Oncogene Proteins c-vav / metabolism
  • Signaling Lymphocytic Activation Molecule Family / metabolism*

Substances

  • Antigens, Differentiation, T-Lymphocyte
  • CD226 antigen
  • CD244 protein, human
  • KLRK1 protein, human
  • NF-kappa B
  • NK Cell Lectin-Like Receptor Subfamily K
  • Proto-Oncogene Proteins c-vav
  • Signaling Lymphocytic Activation Molecule Family
  • VAV1 protein, human