The "bacterial enzyme" discovered more than a decade ago is extremely important for the regulation of many diseases in humans

After pancreatitis recovered, mice lacking Fic were more likely to form scars
in the pancreas.

A new study suggests that an enzyme called Fic, which plays a crucial role in directing cells' response to stress, was discovered
a decade ago at the University of Texas Southwest.
The findings, published in PNAS, could eventually lead to new treatments
for a variety of diseases.

Amanda Casey, Ph.
D.
(left) and Hillery F.
Gray of Orth Lab

"We think of Fic as an autoregulator that regulates how cells respond to stressors
.
If we can control the autoregulator and set it up the way we want it in different tissues, we may one day be able to slow or even stop the progression of some diseases," said Dr.
Amanda Casey, an assistant professor of molecular biology and a former postdoc
in UTSW Orth's lab.
Dr.
Casey co-led the study with Dr.
Kim Orth, a professor of molecular biology and a fellow at
the Howard Hughes Medical Institute.

Fic, originally found in Vibrio parahaemolyticus, which causes food poisoning, has long been a research focus
in Orth's lab.
In 2009, Dr.
Orth and her colleagues published the first paper showing that Fics were involved in a process called AMPylation, in which the enzyme facilitated the transfer of a phosphate and adenosine group to other proteins, altering their activity
.
The researchers soon discovered that animals from worms to humans also have a Fic enzyme
.

Dr.
Kim Orth is a professor of molecular biology and a researcher at the Howard Hughes Institute for Medicine

Studies of fruit flies have shown that Fics appear to be important
for stress recovery and recovery.
A paper published in 2018 by Dr.
Orth and Dr.
Helmut Krämer (UTSW Professor of Neuroscience and Cell Biology) and colleagues showed that if the Fic gene is deleted through genetic engineering, flies that are continuously exposed to bright light suffer permanent damage that can damage their eyes
.
However, the role of this enzyme in mammals is unclear
.

To answer this question, the researchers designed a mouse model
without the Fic gene.
These animals were initially indistinguishable from their nest animals carrying Fics and looked healthy
.
However, when the researchers fasted the animals for 14 hours and then told them to eat as much as they wanted in two hours — a stress source for the pancreas that control blood sugar and produce key digestive enzymes — blood tests in Fic-deficient animals showed higher stress responses
than Fic-carrying animals.
Further research showed that a molecular pathway known as the "folding protein response" (UPR) — which is activated when stressful cells are unable to fold newly generated proteins — is more strongly activated
in Fic-deficient animals.

When given a drug called chlorophyll to a mouse model, the researchers made similar findings
.
Chlorophyll acts on the pancreas, prompting an increase
in the secretion of digestive enzymes.
Although pancreatitis occurred in animals with and without Fic, the condition of animals without this enzyme deteriorated significantly, accompanied by significantly stronger UPR
.
In particular, animals with Fic recovered quickly, but those without Fic developed permanent scars on the pancreas — a sign
of significantly lower resistance to stress.

Dr.
Orth added that uncontrolled cellular stress responses and general reversible responses play a role in many diseases, including cancer, metabolic syndrome, atherosclerosis, retinal degeneration, and various neurodegenerative diseases
.

"If we can determine how the 'pressure autoregulator' is set up, we can turn stress response up or down in a variety of diseases where the stress
response is a factor," she said.