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.

• MeSH
• aktivace lymfocytů MeSH
• buněčná membrána metabolismus   MeSH
• Drosophila melanogaster MeSH
• gating iontového kanálu MeSH
• HEK293 buňky MeSH
• konformace proteinů MeSH
• lidé MeSH
• membránové proteiny metabolismus   MeSH
• mutace MeSH
• proteasy chemie   MeSH
• protein ORAI1 chemie   MeSH
• serinové endopeptidasy metabolismus   MeSH
• signální transdukce MeSH
• stochastické procesy MeSH
• vápník metabolismus   MeSH
• vápníková signalizace fyziologie   MeSH
• vápníkové kanály chemie   MeSH
• vazba proteinů MeSH
• výpočetní biologie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH