Enzyme Adjusts Cell’s Response to Stressors

Texas researchers have discovered that the enzyme Fic plays a role in regulating cellular stress response and say that the findings could be used to develop treatments for diseases like cancer, metabolic syndrome, and neurodegenerative disorders.

Previous research in fruit flies suggested Fic is important for stress resilience and recovery. A study published in 2018 and led by Kim Orth, Ph.D., Professor of Molecular Biology and a Howard Hughes Medical Institute Investigator at University of Texas Southwestern (UTSW) Medical Center and Dr. Helmut Krämer, Ph.D., Professor of Neuroscience and Cell Biology at UTSW, showed that flies constantly exposed to bright light, which damages their eyes, suffered permanent harm if their Fic gene was deleted through genetic engineering.

However, the role of this enzyme in mammals was unclear. In the recent UTSW study—published in PNAS—the researchers engineered a mouse model without a Fic gene. These animals were initially indistinguishable from littermates with Fic and appeared healthy. However, when the researchers fasted the animals for 14 hours and then allowed them to eat as much as they wanted for two hours—a stressor for the pancreas, which controls blood sugar and produces key digestive enzymes—blood work on the Fic-deficient animals showed a much higher stress response than the animals with Fic. Further investigation showed that a molecular pathway called the unfolded protein response (UPR)—which becomes activated when stressed cells can’t keep up with folding newly generated proteins—was more strongly activated in the Fic-deficient animals.

“We think that Fic acts like a thermostat that adjusts a cell’s response to stressors. If we could gain control of that thermostat and set it how we want in different tissues, we might someday be able to slow or even stop progression of some diseases,” says Amanda Casey, Ph.D., Assistant Professor of Molecular Biology and former postdoctoral fellow in the Orth lab at UTSW.

The researchers made similar findings when the mouse models were dosed with a drug called caerulein, which acts on the pancreas to force an increased output of digestive enzymes. Although animals with Fic and those without developed pancreatitis, those without this enzyme had significantly worse disease, accompanied by a significantly stronger UPR.

Interestingly, although animals with Fic had a quick recovery, those without Fic developed permanent scarring in their pancreas. This is a sign of significantly lower resilience to stress, Casey says.

Orth added that an uncontrolled cellular stress response and UPR play a role in many diseases including cancer, metabolic syndrome, atherosclerosis, retinal degeneration, and various neurodegenerative disorders. “If we can determine how the ‘stress thermostat’ is set, we could adjust it up or down in various diseases where stress response is a factor,” she said.