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Novel STIM1-dependent control of Ca2+ clearance regulates NFAT activity during T-cell activation
FASEB J. 2016 Aug 15;30(11) :3878-3886
PMID: 27528628 PMCID: PMC5067253 URL: http://www.ncbi.nlm.nih.gov/pubmed/27528628
AbstractAntigen presentation to the T-cell receptor leads to sustained cytosolic Ca2+ elevation, which is critical for T-cell activation. We previously showed that in activated T cells, Ca2+ clearance is inhibited by the endoplasmic reticulum Ca2+ sensor stromal interacting molecule 1 (STIM1) via association with the plasma membrane Ca2+/ATPase 4 (PMCA4) Ca2+ pump. Having further observed that expression of both proteins is increased in activated T cells, the current study focused on mechanisms regulating both up-regulation of STIM1 and PMCA4 and assessing how this up-regulation contributes to control of Ca2+ clearance. Using a STIM1 promoter luciferase vector, we found that the zinc finger transcription factors early growth response (EGR) 1 and EGR4, but not EGR2 or EGR3, drive luciferase activity. We further found that neither STIM1 nor PMCA4 is up-regulated when both EGR1 and EGR4 are knocked down using RNA interference. Further, under these conditions, activation-induced Ca2+ clearance inhibition was eliminated with little effect on Ca2+ entry. Finally, we found that nuclear factor of activated T-cell (NFAT) activity is profoundly attenuated if Ca2+ clearance is not inhibited by STIM1. These findings reveal a critical role for STIM1-mediated control of Ca2+ clearance in NFAT induction during T-cell activation.-Samakai, E., Hooper, R., Martin, K. A., Shmurak, M., Zhang, Y., Kappes, D. J., Tempera, I., Soboloff, J. Novel STIM1-dependent control of Ca2+ clearance regulates NFAT activity during T-cell activation.
NotesSamakai, Elsie Hooper, Robert Martin, Kayla A Shmurak, Maya Zhang, Yi Kappes, Dietmar J Tempera, Italo Soboloff, Jonathan R01 GM097335/GM/NIGMS NIH HHS/United States R01 GM117907/GM/NIGMS NIH HHS/United States FASEB J. 2016 Aug 15. pii: fj.201600532R.