title: T Cell Receptor-induced Nuclear Factor κB (NF-κB) Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-mediated Calcium Entry.
abstract: T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular Ca(2+) to activate the key transcription factors nuclear factor of activated T lymphocytes (NFAT) and NF-κB. The mechanism of NFAT activation by Ca(2+) has been determined. However, the role of Ca(2+) in controlling NF-κB signaling is poorly understood, and the source of Ca(2+) 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 Ca(2+) via STIM1-dependent Ca(2+) release-activated Ca(2+)/Orai channels. We further show that Ca(2+) 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 Ca(2+) is entirely separate from its upstream control of IκBα degradation, thereby identifying a novel Ca(2+)-dependent distal step in TCR-induced NF-κB activation. Finally, we demonstrate that this control of distal signaling occurs via Ca(2+)-dependent PKCα-mediated phosphorylation of p65. Thus, we establish the source of Ca(2+) required for TCR-induced NF-κB activation and define a new distal Ca(2+)-dependent checkpoint in TCR-induced NF-κB signaling that has broad implications for the control of immune cell development and T cell functional specificity.
authors.affiliation: From the Departments of Pathobiology and.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Departments of Pathobiology and the School of Biomedical Engineering, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Corbett T
authors.initials: CT
authors.lastname: Berry
authors.affiliation: From the Departments of Pathobiology and.
authors.forename: Gordon
authors.initials: G
authors.lastname: Ruthel
authors.affiliation: From the Departments of Pathobiology and.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Madara
authors.affiliation: From the Departments of Pathobiology and.
authors.forename: Katelyn
authors.initials: K
authors.lastname: MacGillivray
authors.affiliation: Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Gray
authors.affiliation: Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Madge
authors.affiliation: Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: McCorkell
authors.affiliation: From the Departments of Pathobiology and.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Beiting
authors.affiliation: the School of Biomedical Engineering, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Uri
authors.initials: U
authors.lastname: Hershberg
authors.affiliation: Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: May
authors.affiliation: From the Departments of Pathobiology and bruce@vet.upenn.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Freedman
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000096:biosynthesis* / Q000235:genetics; D020013:Calcium Signaling / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D000071740:ORAI1 Protein; D010766:Phosphorylation / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1; D013601:T-Lymphocytes / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C498143:RELA protein, human; D011948:Receptors, Antigen, T-Cell; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D051996:Transcription Factor RelA; D002118:Calcium
keywords: NF-κB transcription factor; PKC; T-cell receptor (TCR); calcium; calcium release-activated calcium channel protein 1 (ORAI1); posttranslational modification (PTM); stromal interaction molecule 1 (STIM1)
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