ERstress

ERStress, sometimes written as ER stress, refers to a condition in which the endoplasmic reticulum (ER) experiences an accumulation of unfolded or misfolded proteins, disturbing ER homeostasis. It can be triggered by high protein synthesis load, mutations affecting folding, calcium imbalance, oxidative stress, or lipid perturbations. In response, cells activate the unfolded protein response (UPR) to restore folding capacity and ER function. If the stress is severe or prolonged, it can lead to cell dysfunction and death.

The UPR is mediated by three ER membrane sensors: IRE1, PERK, and ATF6. IRE1 activates an unconventional splicing of XBP1 mRNA, producing a transcription factor that upregulates chaperones and ER-associated degradation (ERAD) components. PERK phosphorylates eIF2α, reducing general translation to lessen the load, while selectively enhancing translation of ATF4, which in turn drives stress response genes. ATF6 moves to the Golgi, is cleaved to release a cytosolic fragment that acts as a transcription factor to increase chaperone and ERAD gene expression.

Together, these pathways aim to increase protein folding capacity, degrade misfolded proteins, and decrease synthesis. If homeostasis cannot be restored, signaling can promote apoptosis through factors such as CHOP, JNK, and caspases in some contexts, contributing to tissue damage.

ER stress is implicated in many diseases, including neurodegenerative disorders, diabetes and metabolic syndrome, cardiovascular disease, and cancer, as well as in aging. Physiologically, ER stress occurs in secretory cells during high-demand periods and in adaptive responses to transient stress.

Biomarkers include BiP/GRP78, CHOP, and XBP1 splicing; detection relies on mRNA and protein assays. Therapeutic strategies aim to modulate the UPR with chemical chaperones, antioxidants, or pathway-specific inhibitors, with ongoing research into clinical relevance and safety.