T cell receptor-induced nuclear factor κb (NF-κB) signaling and transcriptional activation are regulated by STIM1- and Orai1-mediated calcium entry

Xiaohong Liu, Corbett T. Berry, Gordon Ruthel, Jonathan J. Madara, Katelyn MacGillivray, Carolyn M. Gray, Lisa A. Madge, Kelly A. McCorkell, Daniel P. Beiting, Uri Hershberg, Michael J. May, Bruce D. Freedman

Research output: Contribution to journalArticlepeer-review


T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular Ca2+ to activate the key transcription factors nuclear factor of activated T lymphocytes (NFAT) and NF-κB. The mechanism ofNFATactivation by Ca2+ has been determined. However, the role of Ca2+ in controlling NF-κB signaling is poorly understood, and the source of Ca2+ required for NF-κB activation is unknown. We demonstrate that TCR- but not TNF-induced NF-κB signaling upstream of IκB kinase activation absolutely requires the influx of extracellular Ca2+ via STIM1-dependent Ca2+ release-activated Ca2+/Orai channels. We further show that Ca2+ influx controls phosphorylation of the NF-κB protein p65 on Ser-536 and that this posttranslational modification controls its nuclear localization and transcriptional activation. Notably, our data reveal that this role for Ca2+ is entirely separate from its upstream control of IκBκ degradation, thereby identifying a novel Ca2+-dependent distal step in TCR-induced NF-κB activation. Finally, we demonstrate that this control of distal signaling occurs via Ca2+-dependent PKC α-mediated phosphorylation of p65. Thus, we establish the source of Ca2+ required for TCR-induced NF-κB activation and define a new distal Ca2+-dependent checkpoint in TCR-induced NF-κB signaling that has broad implications for the control of immune cell development and T cell functional specificity.

Original languageEnglish
Pages (from-to)8440-8452
Number of pages13
JournalJournal of Biological Chemistry
Issue number16
StatePublished - 15 Apr 2016
Externally publishedYes

Bibliographical note

Funding Information:
The work was supported by National Institutes of Health Grants RO1AI060921 (to B. F.) and RO1HL096642 (to M. M.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'T cell receptor-induced nuclear factor κb (NF-κB) signaling and transcriptional activation are regulated by STIM1- and Orai1-mediated calcium entry'. Together they form a unique fingerprint.

Cite this