Novel STIM1-dependent control of Ca2+ clearance regulates NFAT activity during T-cell activation.

FASEB J 2016 11 15;30(11):3878-3886. Epub 2016 Aug 15.

Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA;

Antigen presentation to the T-cell receptor leads to sustained cytosolic Ca elevation, which is critical for T-cell activation. We previously showed that in activated T cells, Ca clearance is inhibited by the endoplasmic reticulum Ca sensor stromal interacting molecule 1 (STIM1) via association with the plasma membrane Ca/ATPase 4 (PMCA4) Ca 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 Ca 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 Ca clearance inhibition was eliminated with little effect on Ca entry. Finally, we found that nuclear factor of activated T-cell (NFAT) activity is profoundly attenuated if Ca clearance is not inhibited by STIM1. These findings reveal a critical role for STIM1-mediated control of Ca 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 Ca clearance regulates NFAT activity during T-cell activation.

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http://dx.doi.org/10.1096/fj.201600532RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067253PMC
November 2016
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References

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T cell receptor signalling
Lin J. et al.
J. Cell Sci 2001

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