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

Grieve, A. G.; Yeh, Y.-C.; Zarcone, L.; Breuning, J.; Johnson, N.; Strisovsky, K.; Brown, M. H.; Parekh, A. B.; Freeman, M.

doi:10.1101/2020.04.04.025262

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bioRxiv · 10.1101/2020.04.04.025262

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

Grieve, A. G.·Yeh, Y.-C.·Zarcone, L.·Breuning, J.·Johnson, N.·Strisovsky, K.·Brown, M. H.·Parekh, A. B.·Freeman, M.

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Abstract

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 signalling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved, disease-linked proline residue is responsible for RHBDL2 recognising only the active conformation of Orai1, and cleavage by RHBDL2 is required to sharpen switch-like signalling triggered by store-operated calcium entry. Loss of RHBDL2 control of Orai1 causes severe dysregulation of CRAC channel effectors including transcription factor activation, inflammatory cytokine expression and T cell activation. We propose that this seek-and-destroy function may represent an ancient activity of rhomboid proteases in degrading unwanted signalling proteins.

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Grieve, A. G., Yeh, Y.-C., Zarcone, L., Breuning, J., Johnson, N., Strisovsky, K., Brown, M. H., Parekh, A. B., Freeman, M.. 2020-04-05. Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation. https://doi.org/10.1101/2020.04.04.025262

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