November 06, 2018

Shape-shifting ribosomes tune the cellular response to stress

November 06, 2018

Ribosomes help your cells build proteins, based on the instructions provided in genes. So, when ribosomes malfunction, disease is not far behind.

To better understand how cells respond to stressors, scientists at Scripps Research are looking to a new yeast model that reveals how human ribosomes may function in both healthy and diseased states.

The scientists recently discovered that cells can manage stress through a process they dub ribo-tuning. This means cells reprogram themselves by evolving their genes to bind to specialized ribosomes, which are produced under stress conditions. The study, which has implications for better understanding the role of ribosomes in cancer, was published recently in Cell Chemical Biology.

We created the ribo-tuning model in the lab to study how ribosomes decipher information about the amount of protein produced from an mRNA. But it turns out there's evidence in naturally occurring yeast strains that ribo-tuning happens on its own in response to stress in the cell, says senior author Katrin Karbstein, PhD, an associate professor on Scripps Research's Florida campus. This finding suggests to us that this adaptation may be a commonly used mechanism that's been previously underappreciated.

The protein behind ribo-tuning'

The scientists focused on a protein called Rps26, which the Karbstein lab had previously found helps ribosomes select individual genetic messenger molecules, called mRNAs, by recognizing the start of protein sequences and begin building proteins. People with Rps26 deficiencies can develop a bone marrow disorder called Diamond Blackfan anemia, which includes an increased risk of leukemia.

In the new study, the investigators wanted to systematically reprogram protein translation to alter the cellular response to deficiencies in the Rps26 protein. They discovered that with a single point mutation they were able to program yeast cells to change their cell wall composition, activate DNA repair, or differentiate in response to Rps26 deficiency, as well as biological stresses, which produce Rps26 deficiency. The simplicity of these adaptations via a single mutation, together with the finding that some of the changes they made were found in naturally occurring yeast strains, suggest that this ribo-tuning mechanism might be a widespread mechanism to adapt to cellular stress.

Although the research was done in yeast, it has important implications for understanding certain processes in cancer. Both cancer cells and yeast cells are known to change the composition of their ribosomes. And because cancer cells grow and divide very rapidly, they are similar to the samples of yeast that we found that have these types of mutations, says Karbstein.

Karbstein's lab will continue to study other ribosomal proteins in yeast to further decode how proteins are manufactured and mis-manufactured. In addition, they plan to look at the role of Rps26 and other ribosome-related proteins in mammalian cells in culture, with the goal of understanding more about how these proteins may contribute to cancer progression.

Students moved research forward

The new study was also a chance to train the next generation of biomedical researchers. The first author of the study was Max Ferretti, a graduate student in Karbstein's lab. The other author on the study was Jennifer Louise Barre, who at the time she conducted research was a high school student at the nearby Benjamin School.

I knew that working at Scripps would be a once in a lifetime opportunity. I was fortunate enough to work with Dr. Karbstein and also Max who was my mentor, says Barre. Going into this internship I had no idea that I would be fortunate enough to be published and I feel so lucky that I was. I was able to work with some incredible people and expand upon my knowledge of working in a lab environment, which is something I will forever be grateful for.

Karbstein's lab has hosted several high school students over the past few years, thanks to Benjamin School science teacher Renee Szeliga, and this is the second published paper with one of these students as a co-author. This collaboration with Mrs. Szeliga and The Benjamin School has been extremely rewarding for us, says Karbstein. For me personally, it is also important that we open doors for young women as they enter college, and hopefully the scientific workforce.

The study, Translational Reprogramming Provides a Blueprint for Cellular Adaptation, was funded by National Institutes of Health grants R01-GM086451 and F31- GM116406 and a Howard Hughes Medical Institute Faculty Scholar grant.

Integrative Structural & Computational Biology Karbstein, Katrin

LINK:	https://www.scripps.edu/news-and-events/press-room/2018/20181106-ribos...
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