Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation

0549170 - ÚOCHB 2022 RIV US eng J - Článek v odborném periodiku
Grieve, A. G. - Yeh, Y.-C. - Chang, Y.-F. - Huang, H.-Y. - Zarcone, L. - Breuning, J. - Johnson, Nicholas - Stříšovský, Kvido - Brown, M. H. - Parekh, A. B. - Freeman, M.
Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation.
Molecular Cell. Roč. 81, č. 23 (2021), s. 4784-4798. ISSN 1097-2765. E-ISSN 1097-4164
Grant CEP: GA MŠMT(CZ) EF16_019/0000729; GA ČR(CZ) GA21-24456S
Institucionální podpora: RVO:61388963
Klíčová slova: rhomboid protease * CRAC channel * Orai1 * RHBDL2 * transmembrane * calcium * T cell * signalling
Obor OECD: Cell biology
Impakt faktor: 19.328, rok: 2021
Způsob publikování: Open access
https://doi.org/10.1016/j.molcel.2021.10.025

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.
Trvalý link: http://hdl.handle.net/11104/0325187