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Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation
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SYSNO ASEP 0549170 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation Author(s) Grieve, A. G. (GB)
Yeh, Y.-C. (GB)
Chang, Y.-F. (TW)
Huang, H.-Y. (TW)
Zarcone, L. (GB)
Breuning, J. (GB)
Johnson, Nicholas (UOCHB-X) RID, ORCID
Stříšovský, Kvido (UOCHB-X) RID, ORCID
Brown, M. H. (GB)
Parekh, A. B. (GB)
Freeman, M. (GB)Source Title Molecular Cell. - : Cell Press - ISSN 1097-2765
Roč. 81, č. 23 (2021), s. 4784-4798Number of pages 15 s. Language eng - English Country US - United States Keywords rhomboid protease ; CRAC channel ; Orai1 ; RHBDL2 ; transmembrane ; calcium ; T cell ; signalling OECD category Cell biology R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA21-24456S GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000728513200006 EID SCOPUS 85119914778 DOI 10.1016/j.molcel.2021.10.025 Annotation Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2’s recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered by store-operated calcium entry. Loss of RHBDL2 control of CRAC channel activity causes severe dysregulation of downstream CRAC channel effectors, including transcription factor activation, inflammatory cytokine expression, and T cell activation. We propose that this surveillance function may represent an ancient activity of rhomboid proteases in degrading unwanted signaling proteins. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2022 Electronic address https://doi.org/10.1016/j.molcel.2021.10.025
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