T Cell Receptor-induced Nuclear Factor ?B (NF-?B) 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-?B. The mechanism of NFAT activation by Ca(2+) has been determined. However, the role of Ca(2+) in controlling NF-?B signaling is poorly understood, and the source of Ca(2+) required for NF-?B activation is unknown. We demonstrate that TCR- but not TNF-induced NF-?B signaling upstream of I?B 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-?B 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 I?B? degradation, thereby identifying a novel Ca(2+)-dependent distal step in TCR-induced NF-?B activation. Finally, we demonstrate that this control of distal signaling occurs via Ca(2+)-dependent PKC?-mediated phosphorylation of p65. Thus, we establish the source of Ca(2+) required for TCR-induced NF-?B activation and define a new distal Ca(2+)-dependent checkpoint in TCR-induced NF-?B signaling that has broad implications for the control of immune cell development and T cell functional specificity.

SUBMITTER: Liu X 

PROVIDER: S-EPMC4861418 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature