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Journal article
T Cell Receptor-induced Nuclear Factor κB (NF-κB) Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-mediated Calcium Entry
The Journal of biological chemistry, v 291(16), pp 8440-8452
15 Apr 2016
PMID: 26826124
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 of NFAT activation 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 IκBα 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 PKCα-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.
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Details
- Title
- T Cell Receptor-induced Nuclear Factor κB (NF-κB) Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-mediated Calcium Entry
- Creators
- Xiaohong Liu - From the Departments of Pathobiology and.Corbett T. Berry - Drexel UniversityGordon Ruthel - From the Departments of Pathobiology and.Jonathan J. Madara - From the Departments of Pathobiology and.Katelyn MacGillivray - From the Departments of Pathobiology and.Carolyn M. Gray - University of PennsylvaniaLisa A. Madge - University of PennsylvaniaKelly A. McCorkell - University of PennsylvaniaDaniel P. Beiting - From the Departments of Pathobiology and.Uri Hershberg - Drexel UniversityMichael J. May - University of PennsylvaniaBruce D. Freedman - From the Departments of Pathobiology and.
- Publication Details
- The Journal of biological chemistry, v 291(16), pp 8440-8452
- Publisher
- Elsevier
- Grant note
- National Institutes of Health (http://dx.doi.org/10.13039/100000002) RO1AI060921 / National Institutes of Health (http://dx.doi.org/10.13039/100000002)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000374773200011
- Scopus ID
- 2-s2.0-84964978106
- Other Identifier
- 991019167609004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology