An enzyme called Fic, whose biochemical role was discovered at UT Southwestern more than a dozen years ago, appears to play a crucial role in guiding the cellular response to stress, suggests a new study The findings, published in PNAS, could lead to new treatments for several diseases.
We think that Fic acts as a thermostat that adjusts a cell’s response to stressors. If we could control this thermostat and set it the way we want in different tissues, maybe one day we could slow down or even stop the progression of some diseases.”
Amanda Casey, Ph.D., Assistant Professor of Molecular Biology and former postdoctoral fellow in the Orth lab at UTSW
Dr. Casey led this study with Kim Orth, Ph.D., Professor of Molecular Biology and Howard Hughes Medical Institute Investigator.
Originally discovered in the bacterium Vibrio parahaemolyticus known to cause food poisoning, Fic has long been a focus of Orth’s lab. In 2009, Dr. Orth and his colleagues published the first paper showing that Fic is involved in a process called AMPylation, in which this enzyme facilitates the transfer of a phosphate group and adenosine to other proteins, changing their activity. Researchers soon discovered that animals ranging from worms to humans also have a Fic enzyme.
Research in fruit flies suggested that Fic appeared to be important for resilience and recovery from stress. An article published in 2018 by Dr. Orth and Dr. Helmut Krämer, Ph.D., Professor of Neuroscience and Cell Biology at UTSW, and his colleagues showed that flies constantly exposed to bright light, which damages their eyes, suffered permanent damage if their El gene fic was removed by genetic engineering. However, the role of this enzyme in mammals was unclear.
To answer this question, the researchers designed a mouse model without the Fic gene. These animals were initially indistinguishable from their 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, the work of blood in Fic-deficient animals. they showed a much higher stress response than Fic animals. Further research showed that a molecular pathway called the unfolded protein response (UPR), which is activated when stressed cells cannot keep up with the folding of newly generated proteins, was more strongly activated in the Fic-deficient animals.
The researchers made similar discoveries when mouse models were dosed with a drug called cerulein, which acts on the pancreas to force an increase in the production of digestive enzymes. Although animals with Fic and those without developed pancreatitis, those lacking this enzyme had significantly worse disease, accompanied by a significantly stronger UPR.
Interestingly, while animals with Fic recovered quickly, those without Fic developed permanent scarring of the pancreas, a sign of significantly lower resistance to stress, said Dr. Casey.
Dr. Orth added that an uncontrolled cellular stress response and the UPR play a role in many diseases, including cancer, metabolic syndrome, atherosclerosis, retinal degeneration and several neurodegenerative disorders.
“If we can determine how the ‘stress thermostat’ is set, we could adjust it up or down in various diseases where the stress response is a factor,” he said.
Other UTSW researchers who contributed to this study include Hillery F. Gray, Suneeta Chimalapati, Genaro Hernandez, Andrew Moehlman, Nathan Stewart, Hazel A. Fields, Burak Gulen, Kelly A. Servage, Karoliina Stefanius, Aubrie Blevins, Bret Evers and Helmut. Kramer.
Source:
UT Southwestern Medical Center
Journal reference:
Casey, AK, et al. (2022) Fic-mediated AMPylation moderates the unfolded protein response during physiological stress. PNAS. doi.org/10.1073/pnas.2208317119.