Protective prion keeps yeast cells from going it alone

March 28, 2013

Most commonly associated with such maladies as "mad cow disease" and Creutzfeldt-Jakob disease, prions are increasingly recognized for their ability to induce potentially beneficial traits in a variety of organisms, yeast chief among them.

Now a team of scientists has added markedly to the job description of prions as agents of change, identifying a capable of triggering a transition in yeast from its conventional single-celled form to a cooperative, multicellular structure. This change, which appears to improve yeast's chances for survival in the face of hostile , is an epigenetic phenomenon—a heritable alteration brought about without any change to the organism's underlying genome.

This latest finding, reported in the March 28 issue of the journal Cell, has its origins in work begun several years ago in the lab of Whitehead Institute Member Susan Lindquist. In 2009, Randal Halfmann, then a graduate student in Lindquist's lab, identified dozens of proteins in yeast that have the ability to form prions. That research greatly expanded the known universe of prion elements in yeast, but it failed to answer a key question: What function, if any, do these prions actually have?

In search of an answer, Halfmann, now a fellow the University of Texas Southwestern Medical Center, and colleagues in the Lindquist lab attempted to exploit the fact that several of the prion-forming proteins they had identified acted to modify transcription of yeast genes. It stood to reason that if they could identify which genes were being regulated, they might be able to determine the prions' function.

"We looked at the five transcriptional regulators that are known to be prions in yeast, and we found that in fact, only one gene in the entire was regulated by all five ," says Halfmann.

That gene, as it turns out, was FLO11, a key player in multicellularity in yeast. Indeed changes in FLO11 expression have been shown to act as a toggle, switching yeast from spherical to filamentous form. Halfmann notes that FLO11, which has been shown to be regulated by epigenetic elements, is also highly responsive to environmental stress. Knowing that the prion form of a protein is essentially a misfolded form of that protein, and that stressful conditions increase the frequency of protein misfolding and prion formation, the scientists began to consider the possibility that the prions themselves might be among the epigenetic switches influencing the activity of FLO11.

The group focused on one transcription factor known as mot3, finding that yeast cells containing the prion form of this factor, [MOT3+], acquired a variety of multicellular growth forms known to require FLO11 expression. This was a clear indication that prion formation was causing the differentiation of the cells and their subsequent cooperation. But what about the stress aspect of the hypothesis?

By testing yeast cells against a variety of stressors, the scientists discovered that exposure to a concentration of ethanol akin to that occurring naturally during fermentation increased [MOT3+] formation by a factor of 10.They also found that as the cells exposed to ethanol shifted their metabolism to burn surrounding oxygen through respiration, the prions reverted to their non-prion conformation, [mot3-], and the yeast returned to the unicellular state. In essence, prion formation drove a shift to multicellularity, helping the yeast to ride out the ethanol storm.

"What we have in the end is two sequential environmental changes that are turning on a heritable epigenetic element and then turning it off," says Halfmann. "And between those two changes, the prion is causing the cells to acquire a multicellular growth form that we think is actually important for their survival."

Lindquist, who is also a Howard Hughes Medical Institute investigator, has long argued that prions have played a vital role in yeast evolution and has amassed a body of strong supporting evidence.

"We see them as part of a bet-hedging strategy that allows the yeast to alter their biological properties quickly when their environments turn unfavorable," Lindquist says. She also theorizes that prions may play such roles beyond , and her lab intends to take similar approaches in the hunt for prions and prion-like mechanisms that are potentially beneficial in other organisms.

For Lindquist lab postdoctoral scientist Alex Lancaster, who is also an author of the new Cell paper, these latest findings hint at a potentially novel approach to understanding basic mechanisms underlying the complexities of human diseases, including cancer, whose hallmarks include protein misfolding, epigenetic alterations, metabolic aberrations, and myriad changes in cell state, type, and function. Lancaster likens the opportunity to that of opening a black box.

"It's exciting to think that this could become another tool in the toolbox in the study of multicellularity," Lancaster says. "We know that some tumors are a heterogeneous population of cells and we know that tumor cells can evolve within in their environments to help ensure their own survival. This system could help us further understand the role of epigenetic inheritance within tumors and how it might be influencing cell-cell interactions and even affecting the effectiveness of drug therapies."

Explore further: New yeast prion helps cells survive

More information: "Heritable Remodeling of Yeast Multicellularity by an Environmentally Responsive Prion" Cell, March 28, 2013

Related Stories

New yeast prion helps cells survive

April 23, 2012
One of the greatest mysterious in cellular biology has been given a new twist thanks to findings reported in Science. Researchers at the RIKEN Brain Science Institute show that prions, proteins that transmit heritable information ...

Study finds two gene classes linked to new prion formation

May 26, 2011
Unlocking the mechanisms that cause neurodegenerative prion diseases may require a genetic key, suggest new findings reported by University of Illinois at Chicago distinguished professor of biological sciences Susan Liebman.

Cellular stress can induce yeast to promote prion formation

July 23, 2011
It's a chicken and egg question. Where do the infectious protein particles called prions come from? Essentially clumps of misfolded proteins, prions cause neurodegenerative disorders, such as mad cow/Creutzfeld-Jakob disease, ...

Recommended for you

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

Engineered liver tissue expands after transplant

July 19, 2017
Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

Lunatic Fringe gene plays key role in the renewable brain

July 19, 2017
The discovery that the brain can generate new cells - about 700 new neurons each day - has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan ...

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

New animal models for hepatitis C could pave the way for a vaccine

July 19, 2017
They say that an ounce of prevention is worth a pound of cure. In the case of hepatitis C—a disease that affects nearly 71 million people worldwide, causing cirrhosis and liver cancer if left untreated—it might be worth ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.