New Delhi: Researchers have discovered a protein that is responsible for controlling cell growth in yeast. Since humans and yeasts have remarkably similar cellular mechanisms, pinpointing the differences gives drug developers new targets for treatment.
Yeast cells and human immune system cells rely on surprisingly similar chemical reactions to know when to overgrow. Scientists at the University of Arizona have identified subtle differences between two types of cells that could help in the development of antifungal drugs that are able to attack disease-causing yeasts in the body while sparing the immune system.
Their findings, published in the journal eLife, not only have implications for drug development, they provide important insight into the evolution of ancient growth control pathways found in all multicellular organisms.
It is well known in the scientific community that a group of proteins called TORC1 – short for target of rapamycin kinase complex 1 – regulates the growth of cells in everything from humans to yeasts. But researchers have now identified and named the protein that triggers this process in yeast — a nutrient sensor and TORC1 regulator they named Ait1. While functioning normally, Ait1 shuts down TORC1 in yeast when cells are starved for nutrients, inhibiting cell growth. Ait1 is kind of like a hand holding the TORC1, with a finger that reaches the top and turns the TORC1 on and off. How many nutrients are in a cell,” said study co-author Andrew Capaldi, an associate professor in the Arizona Department of Molecular and Cellular Biology and a member of the BIO5 Institute.
The Capaldi lab is interested in determining how cells sense stress and starvation and then decide how fast to grow. Understanding how TORC1 is triggered in different organisms is important for the development of treatments for a variety of diseases.
TORC1 was originally discovered in yeast, but it is also important for the activation of cells in the human immune system to mount a response. When TORC1 is not working, it can trigger the development of various neurological disorders including cancer, diabetes and epilepsy and depression.
“If TORC1 is too active, it can lead to cancer or epilepsy. If it is inactive, it can lead to depression,” Capaldi said. “We call it the Goldilocks regulation.”
But the fact that the human body relies on the same TORC1 pathway as yeast presents a problem. Capaldi said that if scientists develop drugs that stop the growth of disease-causing yeasts by controlling TORC1, “we are in big trouble because TORC1 also controls the growth of human immune cells and more.”
“As an example, you can very easily inhibit yeast growth by using rapamycin – a drug that directly binds to and inhibits TORC1 – in order to fight any infection well,” Capaldi said. Told. “However, the same drug is routinely 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 and not human immune cells. AIT1 has only evolved in the last 200 million years, which is relatively recent in evolutionary terms. A TORC1 regulator called Rheb disappeared from the cells of various organisms about 200 million years ago, right around the same time that AIT1 evolved.
“We showed that some of the ancient TORC1 regulators (including Reb) found in humans are lost in the same yeast that acquired AIT1 200 million years ago,” Capaldi said. “These same ancient regulators have also been lost in the evolution of other single-celled organisms, including many parasites and plants. Therefore, it is very likely that other single-celled organisms acquired new regulators – similar to AIT1 – their own. Now people can go out and find them, because they would also be good drug targets.”