T Cell Receptorinduced Nuclear Factor B Nfb Signaling And Transcriptional Activation Are Regulated By Stim1 And Orai1mediated Calcium Entry Xiaohong Liu by Xiaohong Liu instant download after payment.

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- B. The mechanism of NFAT activation by Ca2 has been determined. However, the role of Ca2
in controlling NF- B signaling is poorly understood, and the
source of Ca2 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 Ca2 via STIM1-dependent Ca2 release-activated Ca2 /Orai channels. We further show that Ca2 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 Ca2 is entirely separate from its
upstream control of I B degradation, thereby identifying a
novel Ca2 -dependent distal step in TCR-induced NF- B activation. Finally, we demonstrate that this control of distal signaling occurs via Ca2 -dependent PKC -mediated phosphorylation of p65. Thus, we establish the source of Ca2 required for
TCR-induced NF- B activation and define a new distal Ca2 -
dependent checkpoint in TCR-induced NF- B signaling that
has broad implications for the control of immune cell development and T cell functional specificity.