Store-operated calcium entry (SOCE) through the Ca2+ release–activated Ca2+ (CRAC) channel is a central mechanism by which cells generate Ca2+ signals and mediate Ca2+-dependent gene expression. The molecular basis for CRAC channel regulation by the SOCE-associated regulatory factor (SARAF) remained insufficiently understood. Here we found that following ER Ca2+ depletion, SARAF facilitates a conformational change in the ER Ca2+ sensor STIM1 that relieves an activation constraint enforced by the STIM1 inactivation domain (ID; aa 475–483) and promotes initial activation of STIM1, its translocation to ER–plasma membrane junctions, and coupling to Orai1 channels. Following intracellular Ca2+ rise, cooperation between SARAF and the STIM1 ID controls CRAC channel slow Ca2+-dependent inactivation. We further show that in T lymphocytes, SARAF is required for proper T cell receptor evoked transcription. Taking all these data together, we uncover a dual regulatory role for SARAF during both activation and inactivation of CRAC channels and show that SARAF fine-tunes intracellular Ca2+ responses and downstream gene expression in cells.
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6 December 2021
Article|
October 27 2021
Bidirectional regulation of calcium release–activated calcium (CRAC) channel by SARAF
Elia Zomot,
1
Department of Biochemistry, Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
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Hadas Achildiev Cohen,
1
Department of Biochemistry, Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
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Inbal Dagan,
Inbal Dagan
1
Department of Biochemistry, Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
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Ruslana Militsin,
Ruslana Militsin
1
Department of Biochemistry, Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
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Raz Palty
Raz Palty
2
Department of Biochemistry, Technion Integrated Cancer Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
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1
Department of Biochemistry, Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
1
Department of Biochemistry, Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
Inbal Dagan
1
Department of Biochemistry, Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
Ruslana Militsin
1
Department of Biochemistry, Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
Raz Palty
2
Department of Biochemistry, Technion Integrated Cancer Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel
Correspondence to Raz Palty: razpalty@technion.ac.il
*
E. Zomot and H. Achildiev contributed equally to this paper.
Received:
April 04 2021
Revision Received:
August 29 2021
Accepted:
September 30 2021
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding
Funder(s):
Rappaport Family Institute for Research in Medical Sciences
Funder(s):
Israel Science Foundation
- Award Id(s): 1048/18
© 2021 Zomot et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2021) 220 (12): e202104007.
Article history
Received:
April 04 2021
Revision Received:
August 29 2021
Accepted:
September 30 2021
Citation
Elia Zomot, Hadas Achildiev Cohen, Inbal Dagan, Ruslana Militsin, Raz Palty; Bidirectional regulation of calcium release–activated calcium (CRAC) channel by SARAF. J Cell Biol 6 December 2021; 220 (12): e202104007. doi: https://doi.org/10.1083/jcb.202104007
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