Abstract
Intracellular Ca2+ is essential for diverse cellular functions. Ca2+ entry into many cell types including immune cells is triggered by depleting endoplasmic reticulum (ER) Ca2+, a process termed store-operated Ca2+ entry (SOCE). STIM1 is an ER Ca2+ sensor. Upon Ca2+ store depletion, STIM1 clusters at ER–plasma membrane junctions where it interacts with and gates Ca2+-permeable Orai1 ion channels. Here we show that STIM1 is also activated by temperature. Heating cells caused clustering of STIM1 at temperatures above 35 °C without depleting Ca2+ stores and led to Orai1-mediated Ca2+ influx as a heat off-response (response after cooling). Notably, the functional coupling of STIM1 and Orai1 is prevented at high temperatures, potentially explaining the heat off-response. Additionally, physiologically relevant temperature shifts modulate STIM1-dependent gene expression in Jurkat T cells. Therefore, temperature is an important regulator of STIM1 function.
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References
Parekh, A.B. & Putney, J.W. Jr. Store-operated calcium channels. Physiol. Rev. 85, 757–810 (2005).
Hogan, P.G., Lewis, R.S. & Rao, A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 28, 491–533 (2010).
Oh-hora, M. & Rao, A. Calcium signaling in lymphocytes. Curr. Opin. Immunol. 20, 250–258 (2008).
Vig, M. & Kinet, J.P. Calcium signaling in immune cells. Nat. Immunol. 10, 21–27 (2009).
Feske, S., Picard, C. & Fischer, A. Immunodeficiency due to mutations in ORAI1 and STIM1. Clin. Immunol. 135, 169–182 (2010).
Putney, J.W. Jr. A model for receptor-regulated calcium entry. Cell Calcium 7, 1–12 (1986).
Lewis, R.S. The molecular choreography of a store-operated calcium channel. Nature 446, 284–287 (2007).
Cahalan, M.D. STIMulating store-operated Ca(2+) entry. Nat. Cell Biol. 11, 669–677 (2009).
Roos, J. et al. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J. Cell Biol. 169, 435–445 (2005).
Liou, J. et al. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr. Biol. 15, 1235–1241 (2005).
Zhang, S.L. et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437, 902–905 (2005).
Luik, R.M., Wang, B., Prakriya, M., Wu, M.M. & Lewis, R.S. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454, 538–542 (2008).
Stathopulos, P.B., Zheng, L., Li, G.Y., Plevin, M.J. & Ikura, M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 135, 110–122 (2008).
Liou, J., Fivaz, M., Inoue, T. & Meyer, T. Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc. Natl. Acad. Sci. USA 104, 9301–9306 (2007).
Yuan, J.P. et al. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat. Cell Biol. 11, 337–343 (2009).
Park, C.Y. et al. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136, 876–890 (2009).
Muik, M. et al. A cytosolic homomerization and a modulatory domain within STIM1 C terminus determine coupling to ORAI1 channels. J. Biol. Chem. 284, 8421–8426 (2009).
Lederman, H.M., Brill, C.R. & Murphy, P.A. Interleukin 1-driven secretion of interleukin 2 is highly temperature-dependent. J. Immunol. 138, 3808–3811 (1987).
Hanson, D.F., Murphy, P.A., Silicano, R. & Shin, H.S. The effect of temperature on the activation of thymocytes by interleukins I and II. J. Immunol. 130, 216–221 (1983).
Hanson, D.F. Fever and the immune response. The effects of physiological temperatures on primary murine splenic T-cell responses in vitro. J. Immunol. 151, 436–448 (1993).
Gern, J.E., Jayman, J.R., Goldberg, L.I., Murphy, P.A. & Lederman, H.M. Temperature is a powerful promoter of interleukin 2 transcription. Cytokine 3, 389–397 (1991).
Hanson, D.F. Fever, temperature, and the immune response. Ann. NY Acad. Sci. 813, 453–464 (1997).
Dhaka, A., Viswanath, V. & Patapoutian, A. Trp ion channels and temperature sensation. Annu. Rev. Neurosci. 29, 135–161 (2006).
Basbaum, A.I., Bautista, D.M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).
Yuan, J.P., Zeng, W., Huang, G.N., Worley, P.F. & Muallem, S. STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nat. Cell Biol. 9, 636–645 (2007).
DeHaven, W.I. et al. TRPC channels function independently of STIM1 and Orai1. J. Physiol. (Lond.) 587, 2275–2298 (2009).
Sun, L., Chen, S., Jiang, J., Xie, Y. & Yu, C. Compounds for inflammation and immune-related uses. World Intellectual Property Organization patent number WO/2006/081391 (2006).
Oh-Hora, M. et al. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nat. Immunol. 9, 432–443 (2008).
Moran, U., Phillips, R. & Milo, R. SnapShot: key numbers in biology. Cell 141, 1262–1262e.1 (2010).
Peier, A.M. et al. A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046–2049 (2002).
Paltauf-Doburzynska, J. & Graier, W.F. Temperature dependence of agonist-stimulated Ca2+ signaling in cultured endothelial cells. Cell Calcium 21, 43–51 (1997).
Oliver, A.E., Baker, G.A., Fugate, R.D., Tablin, F. & Crowe, J.H. Effects of temperature on calcium-sensitive fluorescent probes. Biophys. J. 78, 2116–2126 (2000).
Mercer, J.C. et al. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J. Biol. Chem. 281, 24979–24990 (2006).
Stathopulos, P.B., Li, G.Y., Plevin, M.J., Ames, J.B. & Ikura, M. Stored Ca2+ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: An initiation mechanism for capacitive Ca2+ entry. J. Biol. Chem. 281, 35855–35862 (2006).
Zheng, L., Stathopulos, P.B., Li, G.Y. & Ikura, M. Biophysical characterization of the EF-hand and SAM domain containing Ca2+ sensory region of STIM1 and STIM2. Biochem. Biophys. Res. Commun. 369, 240–246 (2008).
Huang, G.N. et al. STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat. Cell Biol. 8, 1003–1010 (2006).
Wang, Y. et al. STIM protein coupling in the activation of Orai channels. Proc. Natl. Acad. Sci. USA 106, 7391–7396 (2009).
Korzeniowski, M.K., Manjarres, I.M., Varnai, P. & Balla, T. Activation of STIM1-Orai1 involves an intramolecular switching mechanism. Sci. Signal. 3, ra82 (2010).
Hawkins, B.J. et al. S-glutathionylation activates STIM1 and alters mitochondrial homeostasis. J. Cell Biol. 190, 391–405 (2010).
Bandell, M., Macpherson, L.J. & Patapoutian, A. From chills to chilis: mechanisms for thermosensation and chemesthesis via thermoTRPs. Curr. Opin. Neurobiol. 17, 490–497 (2007).
Varga-Szabo, D., Braun, A. & Nieswandt, B. Calcium signaling in platelets. J. Thromb. Haemost. 7, 1057–1066 (2009).
Stiber, J. et al. STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle. Nat. Cell Biol. 10, 688–697 (2008).
Gwack, Y. et al. Hair loss and defective T- and B-cell function in mice lacking ORAI1. Mol. Cell. Biol. 28, 5209–5222 (2008).
Varga-Szabo, D. et al. The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J. Exp. Med. 205, 1583–1591 (2008).
Kenny, G.P. et al. Muscle temperature transients before, during, and after exercise measured using an intramuscular multisensor probe. J. Appl. Physiol. 94, 2350–2357 (2003).
Xiao, B. et al. Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels. J. Neurosci. 28, 9640–9651 (2008).
Grandl, J. et al. Pore region of TRPV3 ion channel is specifically required for heat activation. Nat. Neurosci. 11, 1007–1013 (2008).
Acknowledgements
We thank R.Y. Tsien (University of California, San Diego), P. Shultz (The Scripps Research Institute), S.-S. Tian (Genomics Institute of the Novartis Research Foundation, GNF), A. Parker (GNF), D. Tully (GNF) and S.F. Pan (GNF) for providing reagents; E. Rodrigo, E. Peters, J. Liu, K. Spencer, T. Earley, D. Li and J. Mitsios for experimental help; M. Schmidt for providing advice on GFP-STIM1 puncta analysis; C. Schmedt, M. Cooke, D. Geurini, S.-S. Tian and S. Sanford for discussions; and N. Hong and J. Grandl for reading the manuscript. This research was supported by US National Institutes of Health grants DE016927 and NS046303 and by the Novartis Research Foundation. B.X. is a postdoctoral fellowship recipient from Canadian Institutes of Health Research, Alberta Heritage Foundation for Medical Research and American Heart Association. B.C. is a postdoctoral fellowship recipient from American Heart Association.
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B.X. performed the bulk of the studies. B.C. performed all the electrophysiological studies. J.M. performed quantitative real time–PCR and molecular cloning experiments. B.X., B.C. and A.P. designed the experiments and wrote the paper. All authors read and discussed the paper.
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Supplementary Methods and Supplementary Figures 1–5 (PDF 6519 kb)
Supplementary Video 1
Temperature-dependent changes of GFP-STIM1 puncta and Fura2 ratio in HeLa cells transfected with GFP-STIM1. (MPG 7527 kb)
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Xiao, B., Coste, B., Mathur, J. et al. Temperature-dependent STIM1 activation induces Ca2+ influx and modulates gene expression. Nat Chem Biol 7, 351–358 (2011). https://doi.org/10.1038/nchembio.558
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DOI: https://doi.org/10.1038/nchembio.558
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