What causes endoplasmic reticulum stress?

Endoplasmic reticulum stress is primarily caused by excessive accumulation of misfolded proteins in the endoplasmic reticulum.

The endoplasmic reticulum (ER) is a specialized organelle found in the cytoplasm of eukaryotic cells. It plays a pivotal role in protein synthesis, folding, and dispatch as well as lipid biosynthesis and maintenance of calcium homeostasis.

Protein folding and sorting occurs in the lumen of the endoplasmic reticulum. Only proteins that are properly folded are exported to the Golgi apparatus. Proteins that are incompletely folded are retained in the lumen to be re-processed. The ER attempts to complete the folding process of the proteins left behind. Those that cannot be properly folded are dispatched to the cytosol where they undergo ER- associated degradation.

Under normal conditions, there is an equilibrium between the protein load in the ER and its folding capacity. Excessive accumulation of incorrectly folded proteins of disruption in lipid or calcium syntheses can result in an imbalance in the ER’s homeostasis, causing endoplasmic reticulum stress.

Other causes of ER stress include factors that impair protein glycosylation or disulfide bond formation.