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iRhom pseudoproteases regulate ER stress-induced cell death through IP3 receptors and BCL-2

Author

Listed:
  • Iqbal Dulloo

    (University of Oxford)

  • Peace Atakpa-Adaji

    (University of Cambridge)

  • Yi-Chun Yeh

    (University of Oxford)

  • Clémence Levet

    (University of Oxford)

  • Sonia Muliyil

    (University of Oxford)

  • Fangfang Lu

    (University of Oxford)

  • Colin W. Taylor

    (University of Cambridge)

  • Matthew Freeman

    (University of Oxford)

Abstract

The folding capacity of membrane and secretory proteins in the endoplasmic reticulum (ER) can be challenged by physiological and pathological perturbations, causing ER stress. If unresolved, this leads to cell death. We report a role for iRhom pseudoproteases in controlling apoptosis due to persistent ER stress. Loss of iRhoms causes cells to be resistant to ER stress-induced apoptosis. iRhom1 and iRhom2 interact with IP3 receptors, critical mediators of intracellular Ca2+ signalling, and regulate ER stress-induced transport of Ca2+ into mitochondria, a primary trigger of mitochondrial membrane depolarisation and cell death. iRhoms also bind to the anti-apoptotic regulator BCL-2, attenuating the inhibitory interaction between BCL-2 and IP3 receptors, which promotes ER Ca2+ release. The discovery of the participation of iRhoms in the control of ER stress-induced cell death further extends their potential pathological significance to include diseases dependent on protein misfolding and aggregation.

Suggested Citation

  • Iqbal Dulloo & Peace Atakpa-Adaji & Yi-Chun Yeh & Clémence Levet & Sonia Muliyil & Fangfang Lu & Colin W. Taylor & Matthew Freeman, 2022. "iRhom pseudoproteases regulate ER stress-induced cell death through IP3 receptors and BCL-2," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28930-4
    DOI: 10.1038/s41467-022-28930-4
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