Their research was published ineLife, not only has implications for drug development, but also reveals how an ancient growth-control pathway present in all multicellular organisms has evolved through time.
It is well known to the scientific community that a protein complex called target of rapamycin complex 1 (TORC1) regulates cell growth in everything from humans to yeast. However, the protein that initiates this process in yeast has recently been identified and named Ait1. It is a nutrient sensor and TORC1 regulator. When functioning properly, Ait1 shuts down TORC1 when yeast cells are starved of nutrients, inhibiting cell growth.
“Ait1 is a bit like a hand that holds TORC1 in place, with a finger sticking out to it and turning on depending on how much nutrients the cell has,” said study co-author Andrew Capaldi, an associate professor in the University of Arizona’s Department of Molecular and Cell Biology and a member of the BIO5 Institute. and turn off TORC1.”
The Capaldi lab is interested in determining how cells sense stress and hunger and then decide how fast to grow. Understanding how TORC1 is triggered in different organisms is important for developing treatments for various diseases.
TORC1 was originally discovered in yeast, but it is also critical for activating cells in the human immune system to respond. When TORC1 is not doing its job, it can trigger the development of cancer, diabetes and various neurological disorders, including epilepsy and depression.
“If TORC1 is overactive, it can cause cancer or epilepsy. If it’s not active, then it can cause depression,” Capaldi said. “We call this the ‘Goldilocks’ rule.”
But the fact that the human body relies on the same TORC1 pathway as yeast presents a problem. If scientists develop drugs that inhibit the growth of disease-causing yeast by controlling TORC1, “we’d be in big trouble, because TORC1 also controls the growth of human immune cells and so on,” Capaldi said.
“For example, you can block yeast growth very easily with rapamycin — a drug that binds directly to TORC1 and inhibits TORC1 — so this works well against any infection,” Capaldi said. . “However, the drug is also often used in transplant patients to suppress their immune systems, so it 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 but not human immune cells.
Ait1 has only evolved in the past 200 million years and is relatively new from an evolutionary perspective. About 200 million years ago, a regulator of TORC1 called Rheb appears to have disappeared from the cells of various organisms exactly when Ait1 evolved.
“We show that some of the ancient regulators of TORC1 found in humans, including Rheb, have disappeared in the same yeast that acquired Ait1 200 million years ago,” Capaldi said. “These ancient regulators have also been lost in the evolution of other unicellular organisms, including many parasites and plants. Therefore, it is likely that other unicellular organisms acquired new regulators of their own — similar to Ait1. Now people You can go out and look for them, because they would also be good drug targets.”