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

Cells that cannot cope with persistent endoplasmic reticulum stress will die. Here, the authors show that iRhom pseudoproteases regulate cell death by modulating the ability of BCL-2 to inhibit calcium flow through IP3R channels. 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.

Automated summary

This study reveals that iRhom pseudoproteases regulate cell death by modulating the inhibitory interaction between BCL-2 and IP3 receptors. Loss of iRhoms leads to resistance to ER stress-induced apoptosis. This finding extends the potential pathological significance of iRhoms to diseases dependent on protein misfolding and aggregation.