Response of the Proteome to a Persistent Temperature Rise was Unexpected

Response of the Proteome to a Persistent Temperature Rise was Unexpected

Yeast can adapt and thrive in response to a long-term temperature increase by changing the shape, location, and function of some of their proteins. The unexpected findings highlight the underappreciated plasticity of proteins at the molecular and conformational levels, bringing the power of molecular biology to the organismal response to climate change. The findings of the Buck Institute’s Zhou lab, in collaboration with the Stowers Institute’s Si lab, have been published in Molecular Cell.

Temperature is an unstable parameter in the wild, influencing almost every aspect of life by modifying protein stability and metabolism speed. Previous research has provided extensive knowledge on how acute, short-term temperature increases misfold proteins, revealing how cells respond to such challenges by upregulating molecular chaperones and other stress response proteins to refold/degrade these misfolded proteins in order to help unprepared cells survive, according to Buck Institute Fellow Chuankai “Kai” Zhou, Ph.D. However, Zhou claims that it is unclear whether cells will continue this misfolding-refolding/degradation cycle of proteins when temperature rise becomes a long-term challenge.

“This is a critical question because climate change and global warming threaten to cause temperature increases that will last generations for the majority of the species currently living on Earth,” he said. “Understanding how and whether organisms at the molecular level are prepared for such long-term global warming is critical in order for us to address the future of our ecosystem.”

Common yeast is able to adapt in response to a long-term rise in temperature by changing the shape, location, and function of some of its proteins. The findings demonstrate the unappreciated plasticity in the molecular and bring the power of molecular biology to the organismal response to climate change.

For more than 15 generations, Buck researchers followed and compared yeast cultured at room temperature to cells grown at 95 degrees Fahrenheit (35 degrees Celsius). The higher temperature caused the well-known stress response seen with short-term temperature rise (or heat shock), including protein aggregation and increased expression of protective chaperones. After a few generations of high-temperature growth, researchers saw the cells recover and their growth rate gradually accelerate. Protein aggregates vanished after 15 generations, and many acute stress regulators returned to baseline expression levels. Whole-genome sequencing found no genetic mutations. Zhou says somehow the yeast adapted to the temperature challenge.

Scientists analyzed millions of cells for the entire yeast proteome using unbiased imaging screening and machine-learning-based image analysis and discovered hundreds of proteins that changed their expression patterns, including abundance and subcellular localizations, after the cells adapted to the higher temperatures. “Interestingly, after the yeast acclimated to the new environment, the proteins that tend to be misfolded by acute stress reduced their expression,” Zhou said. “This suggests that reducing the load of thermolabile proteins could be a possible strategy for avoiding the misfolding/refolding cycle under persistent temperature challenge.”

Subcellular localization, according to Zhou, is a determinant of protein function. Under persistent temperature changes, the proteins change their subcellular distribution to either protect themselves from thermal instability or to perform new functions to compensate for the reduction of other thermolabile proteins or both.

Response-of-the-Proteome-to-a-Persistent-Temperature-Rise-was-Unexpected-1
Unexpected proteome plasticity in response to persistent temperature rise

“The most exciting and unexpected changes occur at the sub-molecular level of the proteins,” Zhou explained. “Once the yeast ‘realized’ the heat stress was long-term, they changed a lot.” Some of their proteins changed shape (shape). The current paradigm of gene-protein function research is based on the assumption that a protein has a SINGLE final structure. That is not the case for at least some of the proteins that responded to the temperature change, as we demonstrate.”

This discovery was made possible by Zhou and colleagues’ novel proteomics-structural screening pipeline, which allowed them to identify many proteins that changed shape or conformation after yeast acclimated to their new environment. Importantly, these protein conformation changes were not caused by genetic mutations, and the majority of them did not result in post-translational modifications. Using Fet3p, a multicopper-containing glycoprotein, as an example, the researchers discovered that the protein moved from the endoplasmic reticulum to the cell membrane during thermal acclimation. “What’s most astonishing is that the protein conformation is different as well. It also changes its interacting proteins,” said Zhou.

The researchers discovered that Fet3p, which is produced at different temperatures, has distinct functions in different cellular compartments by examining protein-protein interactions and the associated molecular functions. According to Zhou, thermal acclimation altered protein folding and function, allowing one polypeptide to adopt multiple structures and moonlight functions depending on the growth environment. “These results together show the plasticity of the proteome and reveal previously unknown strategies available to organisms facing long-term temperature challenges,” he says. For simple organism like yeast, which has very limited alternative splicing, such proteome plasticity, or alternative folding of proteins induced by environmental conditions, allows this organism to survive an amazingly broad range of harsh habitats.”

While Zhou is ecstatic about the discovery of an evolutionary-encoded strategy that allows yeast to adapt to different temperatures, he cautions that resilience cannot be assumed. “We know there is a limit to plasticity—the yeast will die above a certain temperature.” Our hope is that this research will allow us to learn from Mother Nature about how organisms adapt to climate change by utilizing the encoded plasticity of their proteins. Some species have survived multiple cycles of climate change throughout Earth’s history, and their genomes/proteomes may have learned how to adapt to such changes.

At the same time, many species are new to climate change and are likely to become extinct as a result of the current global warming. We are eager to contribute to urgent molecular questions and welcome collaborations.”

Zhou intends to continue delving into the molecular details of what happens inside cells during long-term temperature changes, and he intends to include simple animals in his protein plasticity research. He will also investigate the effects of temperature change on aging.

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