New Study Finds Heat Shock Can Drive Changes in Protein Modifications

The planet is getting hotter, and life will need to adapt to rising temperatures to survive. One way that cells adapt to changing conditions is by synthesizing new proteins. That works well when the environment changes slowly, but if a crisis hits, like a sudden temperature increase, cells cannot wait for new proteins to be built. Instead, cells rely on chemical modifications that can rapidly turn proteins on or off, similar to how a light can be turned on or off without having to buy or throw away a bulb each time.  

Understanding the mechanisms by which these chemical modifications impact cellular health could pave the way for better therapeutics. A recent study led by the U of A and published in Genome Biology focused on a type of chemical modification called acetylation.  

Thinking about what acetylation is — a chemical modification to an existing protein — can be a little abstract. First author on the paper, Rebecca Hardman-Kavanaugh, who conducted the research as a Ph.D. student in cell and molecular biology at the U of A, offers a metaphor for understanding the process: 

Think of the cell as a tiny factory. There are a range of things that need to be done to make the factory function, and what does the work are proteins. They are like robots with a pre-programmed job to do. But in the event of an emergency — say, a heat shock — the factory's priorities change. Some tasks must be dropped and new ones taken on to assist with survival. The cell doesn't just make new robots. It reprograms old ones to address the emergency. One switch that signals that reprogramming appears to be acetylation. 

"One thing that has emerged is that defects in global acetylation correlate with different diseases," said Jeffrey Lewis, an associate professor of biological sciences who was the principle investigator on the project and Hardman-Kavanaugh's Ph.D. adviser. "People with heart disease, their global acetylation patterns differ in their hearts than healthy individuals. And it's the same for a number of things ranging from Parkinson's disease to cancer." 

The interdisciplinary team showed that when yeast cells experience high temperatures, hundreds of proteins change in the amount of protein acetylation. The team's hypothesis is that the cells are rapidly activating the protein functions the cell needs to survive — prioritizing the most important — while turning off the ones it does not need. 

Acetylation as a protein modification was first discovered more than 60 years ago and was long thought to only control gene expression, or determining what proteins get made in the first place. More recently, scientists have discovered that thousands of proteins with diverse functions are acetylated. For the vast majority of these proteins, the role of acetylation is unclear. Some researchers have even argued that acetylation may be chemical "noise" with no function at all.  

The team's findings argue against that, at least for a subset of proteins that change in their level of acetylation during heat stress. They found that acetylation changes are much more likely to occur on proteins that the cell needs during stress. They also found that some key proteins have multiple acetylation sites that change in opposite directions, with acetylation increasing on one part of a protein and decreasing on another, suggesting that there is sophisticated and precise regulation of protein activity that is hard to explain as mere noise.  

Because acetylation exists in all life, including humans, these findings will likely translate into our understanding of how cells in other organisms respond to stressful conditions.  

Lewis' lab at the U of A studies how cells adapt and even thrive in the face of environmental stresses like heat. Lewis noted that a better understanding of the relationship between acetylation and cellular modification could open the door to new therapeutics. 

If researchers can tease out what the acetylation patterns in yeast proteins are telling us about stress responses, Lewis said, it has the potential to tell us what is happening in humans. 

Lewis also noted that this work could not have been accomplished without the support of a grant from the National Science Foundation, which is the premier agency that supports fundamental research in the U.S. 

Additional authors on the paper include Aaron J. Storey, Tara N. Stuecker, Stephanie E. Hood, Gregory A. Barrett-Wilt, Venkata R. Krishnamurthi, Yong Wang, Stephanie D. Byrum, Samuel G. Mackintosh, Rick D. Edmondson, Wayne P. Wahls and Alan J. Tackett. Stuecker, Hood, Krishnamurthi and Wang are all affiliated with the U of A.