The unfolded protein response in health and disease.

The endoplasmic reticulum (ER) is the principal cellular organelle in which correct folding and maturation of transmembrane, secretory, and ER-resident proteins occur. Research over the past decade has demonstrated that mutations in proteins or agents/conditions that disrupt protein folding adversely affect ER homeostasis, leading to ER stress. This in turn initiates the unfolded protein response (UPR), an integrated intracellular signalling pathway that responds to ER stress by increasing the expression of ER-resident molecular chaperones, attenuating global protein translation and degrading unfolded proteins. Failure to relieve prolonged or acute ER stress causes the cell to undergo apoptotic cell death. Recent groundbreaking studies have provided compelling evidence that ER stress and UPR activation contribute to the development and progression of human disease, including neurodegenerative disorders, diabetes, obesity, cancer, and cardiovascular disease. Furthermore, the ability of the UPR to modulate oxidative stress, inflammation, and apoptosis provides important cellular clues as to how this evolutionarily conserved cellular-stress pathway maintains and responds to both normal physiologic and pathologic processes. In this Forum issue, many aspects of the UPR are reviewed in the context of how ER stress and UPR activation influence human disease. This current information provides a solid foundation for future investigations aimed at targeting the UPR in an attempt to reduce the risk of human disease.