![]() ![]() Although the ER exists in virtually all mammalian cells, the relative amounts of ER and the demands placed on this organelle are quite different between tissues. This upsets the normal ER homeostasis and induces a signaling pathway called the unfolded protein response (UPR), which serves to alleviate the stress, or alternatively, to eliminate the affected cells to protect the organism ( 60, 104). However, if the amount of proteins to be folded exceeds the capacity of the folding machineries, unfolded proteins will accumulate in the ER. Only proteins that fulfill quality-control standards are allowed to exit the ER and travel farther along the secretory pathway toward their final destinations ( 25). Unlike the cytosol, it also possesses an oxidizing environment, which favors intra- and intermolecular disulfide bond formation, and millimolar concentrations of Ca 2+ that pose unusual complications for folding. It contains high concentrations of molecular chaperones, folding enzymes, and ATP, which aid proper maturation of proteins. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at To prepare these nascent proteins properly for an extracellular fate, the ER lumen possesses a unique environment that is specialized for high-fidelity protein folding and assembly ( 33, 43). HeLa cells were transfected with a lymphoid-specific resident ER protein, pERpl, and visualized with a polyclonal pERp1 antiserum followed by FITC-conjugated anti-rabbit Ig antiserum. The ER is a membrane network that reaches throughout the cells. Although the methods used to deal with this amount of oxidative stress are not well understood, recent research suggests that different types of cells use distinct strategies and that the unfolded protein response (UPR) is a critical component of the defense. Dedicated secretory tissues like the pancreas and plasma cells have been estimated to form up to 3–6 million disulfide bonds per minute, which would be expected to result in the production of the same number of molecules of ROS. Thus, each disulfide bond that forms during oxidative folding should produce a single reactive oxygen species (ROS). Recent experimental data reveal that the formation of disulfide bonds does not occur spontaneously but results from the enzymatic transfer of disulfide bonds through a number of intermediate proteins, with molecular oxygen serving as the terminal electron acceptor. The environment of the ER is oxidizing, which supports the formation of intra- and interchain disulfide bonds that serve to stabilize the folding and assembly of nascent proteins. All eukaryotic cells possess an endoplasmic reticulum (ER), which is the site for synthesizing proteins that populate the cell surface or extracellular space.
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