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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.

Original publication

DOI

10.1016/j.molcel.2021.10.025

Type

Journal article

Journal

Mol Cell

Publication Date

02/12/2021

Volume

81

Pages

4784 - 4798.e7

Keywords

CRAC channel, Orai1, RHBDL2, T cell, calcium, rhomboid protease, signalling, transmembrane, Animals, Calcium, Calcium Channels, Calcium Signaling, Cell Membrane, Computational Biology, Drosophila melanogaster, HEK293 Cells, Humans, Ion Channel Gating, Lymphocyte Activation, Membrane Proteins, Mutation, ORAI1 Protein, Peptide Hydrolases, Protein Binding, Protein Conformation, Serine Endopeptidases, Signal Transduction, Stochastic Processes