eLife's newly discovered protein could be used to produce life-saving antifungal drugs

Like bacteria, yeast is everywhere, even in and around
us.
And, just like bacteria, you get infected with yeast and get sick
.
About 150 million people are infected with yeast each year and about 1.
7 million people die, especially those with
low immunity.

Yeast cells and human immune system cells rely on strikingly similar chemical reactions to know when to grow
.
Scientists at the University of Arizona have identified subtle differences between the two cell types, which may help boost the development of antifungal drugs that are able to attack disease-causing yeast in the body while protecting the immune system
.

Their findings, published in the journal eLife, not only have implications for drug development, but also provide important insight into the evolution of an ancient growth control pathway found in all multicellular organisms
.

The scientific community knows that a combination of proteins called TORC1 — short for rapamycin kinase complex 1 target — controls the growth
of all cells, from humans to yeast.
But researchers have now identified and named the protein in yeast that triggers the process — a nutrient sensor and TORC1 regulator — which they named Ait1
.
When working properly, when cells lack nutrients, Ait1 shuts down TORC1 in yeast, preventing cell growth
.

Andrew Capaldi, an associate professor in the Department of Molecular and Cell Biology at the University of Arizona and a member of the BIO5 Institute and co-author of the study, said: "Ait1 is a bit like a hand holding TORC1, reaching over it with one finger and turning TORC1
on or off depending on how much nutrients are in the cell.
"

The Capaldi lab is interested in determining how cells sense stress and hunger and then determine the rate of
growth.
Understanding how TORC1 is triggered in different organisms is important
for developing treatments for various diseases.

TORC1 was originally found in yeast, but it is also essential
for activating cells in the body's immune system to produce a response.
When TORC1 doesn't work properly, it can trigger cancer, diabetes, and various neurological disorders, including epilepsy and depression
.

"If TORC1 is overactive, it can trigger cancer or epilepsy
.
If it's not active enough, it can lead to depression," Capaldi said
.
"We call it blonde supervision
.
"

But the fact that the human body relies on the same TORC1 pathway as yeast raises a problem
.

If scientists develop drugs that inhibit the growth of disease-causing yeast by controlling TORC1, Capaldi said, "we're going to be in big trouble, because TORC1 also controls the growth
of human immune cells and so on.
" ”

Capaldi said: "For example, you can easily stop the growth of yeast with rapamycin, a drug that directly binds to and inhibits TORC1, so that you can fight any infection
very well.
" "However, transplant patients often use the same drugs to suppress their immune systems, so this would be a disaster
.
"

The researchers found that while the TORC1 pathway is very similar in yeast and humans, humans do not rely on Ait1 to regulate TORC1
.
Therefore, drugs that specifically target Ait1 should inhibit the growth of yeast, not the growth
of human immune cells.

Ait1 only evolved in the last 200 million years, which is relatively recent in terms of
evolution.
About 200 million years ago, a TORC1 regulator called Rheb seemed to disappear from the cells of various organisms, and this is exactly when Ait1 evolved
.

Capaldi said: "We found that some of the ancient TORC1 regulators found in humans, including Rheb, were
lost in yeast that obtained ait12 200 million years ago.
" "During the evolution of other single-celled organisms, including many parasites and plants, these ancient regulators also disappeared
.
So it's quite possible that other single-celled organisms have acquired new regulators — similar to Ait1 — of their own
.
Now people can go out and look for them because they will also be good drug targets
.
”

Capaldi co-authored the study with Xiangxia Luo, a research expert at Capaldi's lab, and two University of Arizona alumni, who are the lead author of the study, Ryan Wallace, who received his Ph.
D.
in biochemistry and molecular biology in 2021 and is now a scientist at Aviva Systems Biologics in San Diego; Eric Lu, who earned his bachelor's degree in molecular and cell biology and biochemistry in 2021, is currently pursuing a PhD and medical degree from
the University of Washington.

The researchers have filed a patent for their discovery through the Tech Launch Arizona as a target for antifungal compounds
.
The Arizona Tech Launch Center is the university office
that commercializes university innovations.

Ait1 regulates TORC1 signaling and localization in budding yeast