Syndicate content

Research Reveals a Physiologic Function for Prion-Like Domains in Cell’s Adaptation to, and Survival from, Environmental Stress

Prions are self-propagating protein aggregates that can be transmitted between cells. The aggregates are associated with human diseases. Indeed, pathological prions cause mad cow disease and, in humans, Creutzfeldt-Jakob disease. The aggregation of prion-like proteins is also associated with neurodegeneration as in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The regions within prion-like proteins that are responsible for their aggregation have been termed prion-like domains. Despite the important role of prion-like domains in human diseases, a physiological function has remained enigmatic. Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), the Biotechnology Center of the TU Dresden (BIOTEC), and Washington University in St. Louis, USA have now identified, for the first time, a benign, albeit biologically relevant, function of prion domains as protein-specific stress sensors that allow cells to adapt to and survive environmental stresses. Uncovering the physiological function is an essential first step towards closing a gap in understanding the biological role of prion-like domains and their transformation into a pathological disease-causing state. The discoveries were published in the January 5, 2018 issue of Science. The article is titled “Phase Separation of a Yeast Prion Protein Promotes Cellular Fitness.” The aggregation of prion-like proteins is associated with human diseases. Their infectious behavior is comparable to the spread of a viral infection. This raises the question of why evolution has kept these proteins around: are these sequences good for anything? In its study, the team around research group leader Professor Simon Alberti from the MPI-CBG focused on the yeast prion protein Sup35, which has a long-standing history as a role model for prion research. The scientists found that the prion-like domain of Sup35 acts like a stress sensor that triggers the formation of protective protein droplets and gels when cells are exposed to harsh conditions. When cells are stressed, for example because they are starved of nutrients, their energy level drops. This leads to a decrease of the cytosolic pH value; that is, the cells acidify. In response, cell division stops, the metabolism shuts down, and cells enter into stand-by mode. When the stress is over, cells must rapidly reprogram their metabolism and restart growth and division. Professor Alberti and his colleagues found that the Sup35 prion-like domain is important for stress survival. "We found that cells lacking the prion domain show a growth defect when recovering from stress,” summarizes Titus Franzmann, the first author of the study. The scientists discovered that the prion-like domain of Sup35 senses the acidic pH of the cytosol and then drives the formation of protein droplets that protect Sup35 from damage.

"To store the protein, the droplets can even advance into a gel-like structure,” says co-author Marcus Jahnel from the biophysics group of Professor Stephan Grill at the BIOTEC. These protein droplets, which form in the cytoplasm similar to condensing water droplets, can dissolve again, enabling the cell to reuse the Sup35 protein when the cell restarts growth.

Additionally, colleagues from Washington University in St. Louis predicted the sequences of the amino acids responsible for Sup35 sensing changes in the cytoplasmic pH value. In this context, Dr. Rohit Pappu, the Edwin H. Murty Professor of Biomedical Engineering at Washington University, noted that: "Uncovering the molecular components that confer these adaptive abilities of Sup35 has also important implications for understanding cells on a molecular level and adopting these principles for building synthetic systems.”

From an evolutionary standpoint, the Sup35 condensates are very interesting, because they are conserved among distantly related yeast that diverged almost 400 million years ago. This suggests that droplet and gel formation may be an ancestral function of the Sup35 prion-like domain.

Franzmann concludes: "The study suggests that prion domains are protein-specific stress sensors that allow cells to respond to specific environmental conditions. In that way, we could show for the first time a positive function of a prion domain that has often only been associated with disease-causing aggregates. So maybe that's the reason why evolution has kept them for so long."

[Press release] [Science abstract]