Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation
Year: 2021
Type: article
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 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.
Source: Molecular Cell
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $8,900
Awards: G12500569, G1275137895, G1475843010, G176604203, G1767254865, Regulation of store-operated calcium entry by rhomboid intramembrane proteolysis, G277992333, G291036901, G3382653560, G3490171961, G4131035492, G4756395926, The control of signalling by members of the rhomboid-like superfamily., G5916014575, G7363506711, Roles of the rhomboid intramembrane protease RHBDL2 in lung epithelial homeostasis and pathology of idiopathic pulmonary fibrosis, Rhomboid-like proteins: from molecular principles to pathophysiological significance, G8482349370
OpenAlex ID: W3014579223