The Endoplasmic Reticulum As the Extracellular Space Inside the Cell: Role in Protein Folding and Glycosylation

Significance: Proteins destined to secretion and exposure on the cell surface are synthesized and processed in the extracellular-like environment of the endoplasmic reticulum (ER) of higher eukaryotic cells. Compartmentation plays a crucial role in the post-translational modifications, such as oxidative folding and N-glycosylation in the ER lumen. Transport of the required intermediates across the ER membrane and maintenance of the luminal redox conditions and Ca2+ ion concentration are indispensable for appropriate protein maturation. Recent Advances: Cooperation of enzymes and transporters to maintain a thiol-oxidizing milieu in the ER lumen has been recently elucidated. Ca2+-dependence of certain ER chaperones is a subject of intensive research. Critical Issues: Mounting evidence supports the existence of a real barrier between the ER lumen and the cytosol. The unique set of enzymes, selection of metabolites, and characteristic ion and redox milieu of the luminal compartment strongly argue against the general permeability of the ER membrane. Future Directions: Alterations in the luminal environment can trigger the unfolded protein response, a common event in a variety of pathological conditions. Therefore, redox and calcium homeostasis and protein glycosylation in the ER provide novel drug-targets for medical treatment in a wide array of diseases. Antioxid. Redox Signal. 16, 1100-1108.