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.
Highlights
The folding capacity of membrane and secretory proteins in the endoplasmic reticulum (ER) can be challenged by physiological and pathological perturbations, causing ER stress
As expected, prolonged ER stress induced by treatment with tunicamycin or brefeldin A caused wildtype cells to die, as measured by double staining with annexin V and propidium iodide
Deletion of iRhom[2] in BV2a mouse microglia cells, which have endogenously low expression of iRhom[1], showed a significant reduction in PARP cleavage upon tunicamycin exposure (Supplementary Fig. 1c). Together these results demonstrate that iRhoms participate in ER stress-induced cell death across multiple mammalian cell types
Summary
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. Like other members of the rhomboid-like superfamily, a core molecular function of iRhoms is the specific recognition of transmembrane domains (TMDs) of interacting client proteins[6] They have been implicated in a number of different cellular control processes but are best characterised as regulatory cofactors of the metalloprotease ADAM17, and of inflammatory and growth factor signalling[2,5,7]. Disturbance of the equilibrium between protein biosynthesis, folding, maturation and onward trafficking leads to potentially toxic accumulation of unfolded or misfolded proteins, creating a state of ER stress This triggers an adaptive mechanism called the unfolded protein response (UPR), which restores ER homoeostasis and promotes cellular survival[15].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
