ArticleMolecular cell2021
Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation.
Article in Molecular cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 18 citations in OpenAlex.
- Rhomboid protease RHBDL2 is a calcium-activated suppressor of EGFR signalling in keratinocytes.Cellular and molecular life sciences : CMLS · 2026Article
- Membrane Protein Insertion in Cells: Principles, Pathways, and Quality Control.Chemical reviews · 2026Review
- RHBDL2 drives lipid metabolic reprogramming in osteosarcoma via USP3-mediated deubiquitination of PPT1.Cell death & disease · 2026Article
- Membrane-embedded polar residues target membrane proteins for degradation by the quality control protease FtsH.Nature communications · 2026Article
- Rhomboid protease Rhbdl2 regulates macrophage recruitment and wound regeneration in zebrafish.bioRxiv : the preprint server for biology · 2026Article
- Store-operated calcium entry-based targets for novel cancer therapeutic development.The Journal of pharmacology and experimental therapeutics · 2025Review
- Optimization and Characterization of the Antimalarial Activity ofJournal of medicinal chemistry · 2025Article
- Rhomboid-mediated cleavage of the immune receptor XA21 protects grain set and male fertility in rice.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- 4-Oxo-β-lactams as Covalent Inhibitors of the Mitochondrial Intramembrane Protease PARL.ACS medicinal chemistry letters · 2024Article
- The Endoplasmic Reticulum and the Fidelity of Nascent Protein Localization.Cold Spring Harbor perspectives in biology · 2023Review
- RHBDL2 promotes the proliferation, migration, and invasion of pancreatic cancer by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway.Cell death & disease · 2022Article
- The Orai1-AC8 Interplay: How Breast Cancer Cells Escape from Orai1 Channel Inactivation.Cells · 2021Review
- More Than Just Simple Interaction between STIM and Orai Proteins: CRAC Channel Function Enabled by a Network of Interactions with Regulatory Proteins.International journal of molecular sciences · 2021Review
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Authors and funding
11 authors at 2 institutions in 2 countries.
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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 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.
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