By shedding light on how cells deal with stress, a new study led by The Children’s Hospital of Philadelphia’s Yair Argon, PhD, could lay the foundations for future therapies. The study, which identified an enzyme the body uses to ameliorate endoplasmic reticulum stress, was published recently in Molecular Cell.
An organelle found in all eukaryotic cells, the endoplasmic recticulum (ER) plays an important role in the manufacture and delivery of enzymes, lipids, and proteins. When stress is placed on the ER — due to such things as environmental factors, hypoxia, and viral infections — cells’ ability to synthesize, fold, and mature proteins can be impaired.
This condition of ER stress has been associated with a wide range of diseases, including amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), bipolar disorder, cancer, diabetes, and heart disease.
Cells’ response to ER stress is the unfolded protein response (UPR), in which sensors are activated in an attempt to return the cell to homeostasis or, failing that, to induce apoptosis. In the Molecular Cell study, Dr. Argon and colleagues investigated the regulation of the UPR sensors.
Working with two postdoctoral fellows, Davide Eletto, PhD, and Daniela Eletto, PhD, as well as a graduate student, Devin Dersh, and in collaboration with Drexel University’s Tali Gidalevitz, PhD, the researchers found that the activity of one major sensor — inositol-requiring enzyme 1α (IRE1α) — is normally regulated by the enzyme protein disulfide isomerase A6 (PDIA6).
“We showed that this mechanism for limiting ER stress signaling and maintaining it within a physiologically appropriate range operates in cells in culture and also in an animal model,” Dr. Argon said. In PDIA6’s absence, several of the activities of IRE1α are exaggerated and PDIA6-deficient cells are more sensitive to ER stresses such as the presence of misfolded mutant insulin. Conversely, when there is excess activity of PDIA6, IRE1α activity terminates earlier, because PDIA6 modifies the activated sensor.
While the current study is basic, the research nonetheless “has important implications for many areas of physiology and multiple diseases,” Dr. Argon noted. “Because PDIA6 is an enzyme, one can imagine that its activity can be targeted by future development of small molecules, which may either inhibit it, when it is desirable to exacerbate the response and cause cell death, or activate it, when it is desirable to dampen the response.”
“Therefore, there are clear translational research avenues to be explored,” he added.
To read more about this study, see Molecular Cell