In normal functioning cells, endoplasmic reticulum (ER) is the major control site for folding, modification, and trafficking of secretory and cell-surface proteins. ER also plays a crucial role in the maintenance of cellular calcium homeostasis. Since ER is a key organelle in the cell; ER stress-mediated cell death can be associated with numerous diseases including Alzheimer disease, Parkinson disease, neuronal damage-induced ischemia, prion disease, cystic fibrosis, and diabetes mellitus. ER stress is a consequence of complex mechanisms which several cellular pathways interact with each other simultaneously. The two most important initiating points for ER stress-mediated cell death are; transcription factor CHOP/GADD153 and ER membrane protein kinase (IRE1). ER stress triggers proteolytic cleavage of caspase-12 and caspase-4, both of which are localized at the cytoplasmic side of the ER membrane to initiate the mechanism of cell death. Thus, ER stress and mitochondrial apoptosis are linked via caspase-12, which is seen in several degenerative diseases.
Part of the book: Programmed Cell Death