Unknown,Transcriptomics,Genomics,Proteomics

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T Cell Receptor-Induced NF-kB 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 calcium (Ca2+) to activate the key transcription factors NFAT and NF-ÎºB. The mechanism of NFAT activation by Ca2+ has been determined; however, the role of Ca2+ in controlling NF-ÎºB signaling is poorly understood and the source of Ca2+ required for NF-ÎºB activation is unknown. We demonstrate that TCR- but not TNF- induced NF-ÎºB signaling upstream of IÎºB kinase (IKK) activation absolutely requires the influx of extracellular Ca2+ via STIM1-dependent CRAC/Orai channels. We further show that Ca2+ influx controls phosphorylation of the NF-ÎºB protein p65 on Ser536 and that this post- translational 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 IÎºBÎ± degradation, thereby identifying a novel Ca2+- dependent distal step in TCR-induced NF-ÎºB activation. Finally, we demonstrate that this control of distal signaling occurs via Ca2+-dependent PKCk-mediated phosphorylation of p65. Thus, we establish the source of Ca2+ required for TCR induced NF-kB activation and we define a new distal Ca2+-dependent checkpoint in TCR-induced NF-kB signaling that has broad implications for the control of immune cell development and T cell functional specificity. 3 treatments were analyzed, with biological replicates for each treatment. In addition, three timepoints (1 hour, 4 hour, and 8 hour) were examined for each treatment, as well as an untreated control. In total 19 samples were analyzed

ORGANISM(S): Homo sapiens

SUBMITTER: daniel beiting

PROVIDER: E-GEOD-76804 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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T Cell Receptor-Induced NF-kB Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-Mediated Calcium Entry

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