Relieving Endoplasmic Reticulum Stress May Prevent Some Types of Chronic Disease

A team of cell biologists has identified an enzyme that protects cells against endoplasmic reticulum (ER) stress and prevents the apoptosis that characterizes such chronic diseases as Wolfram syndrome, diabetes, heart disease, and Parkinson's disease.

Among its many activities, the endoplasmic reticulum folds and modifies newly formed proteins so they have the correct three-dimensional shape to function properly. The ER also helps transport proteins, fats, and other materials to specific sites within the cell or to the cell surface. When placed under certain types of stress, the ER can leak molecules into other parts of the cell, which can trigger the apoptotic pathway that leads to cell death and eventually to organ dysfunction.

Investigators at Washington University School of Medicine (St. Louis, MO, USA) reported in the June 23, 2015, on line edition of the journal Science Signaling that they had identified a mechanism by which the enzyme IRE1 conferred protection against ER stress-mediated cell death. In humans, IRE1 is called "ER to nucleus signaling 1 protein." This protein possesses intrinsic kinase activity and an endoribonuclease activity, and it is important in altering gene expression as a response to ER-based stress signals.

The investigators found that IRE1 signaling prevented ER membrane permeabilization mediated by the proteins Bax and Bak and cell death in cells experiencing ER stress. In response to ER stress, cells deficient in IRE1 were found to be susceptible to leakage of ER contents, which was associated with the accumulation of calcium in mitochondria, oxidative stress in the cytosol, and ultimately cell death.

Senior author Dr. Fumihiko Urano, professor of medicine at Washington University School of Medicine, said, "We believe the enzyme we identified may provide us with a target to protect many types of cells from a death cascade that leads to those different, seemingly unrelated disorders. It is clear from our experiments that this enzyme can keep the membrane in the cell from becoming permeable and leaking. We think it may be possible to prevent Wolfram syndrome and other diseases related to this type of cellular stress by targeting the enzyme to make the membrane stronger."

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Washington University School of Medicine