Translational control in the endoplasmic reticulum stress response.

From the perspective of protein biosynthesis, the endoplasmic reticulum (ER) can be viewed as a processing plant for folding and posttranslational modification of secreted and integral membrane proteins. At any given time, the load of client proteins that the ER must handle is set by developmental programs and modulated by physiological considerations. Specific signaling pathways and effector mechanisms have evolved to deal with the temporal and developmental variation in ER load experienced by different cells in mutlicellular organisms. The upstream signal that activates these pathways is referred to as ER stress and is defined functionally as an imbalance between the load of client proteins facing the ER and the organelle’s ability to process that load. ER stress can be provoked by a variety of pathophysiological conditions, for example, ischemia, hyperhomocystinemia, viral infections, and mutations that impair client protein folding (1–4). However, the phenotypes of mutations affecting components of the ER stress-response machinery reveal that ER stress is also a normal physiological phenomenon (reviewed in ref. 5).

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