Peering inside Cells to See How They Respond to Stress
Published:04 Jan.2024    Source:University of Chicago
Ali and his team studies study how cells adapt to stressful and complex environments, including the heat shock response. They combined several new imaging techniques to show that in response to heat shock, cells employ a protective mechanism for their orphan ribosomal proteins -- critical proteins for growth that are highly vulnerable to aggregation when normal cell processing shuts down -- by preserving them within liquid-like condensates. Once the heat shock subsides, these condensates get dispersed with the help of molecular chaperone proteins, facilitating integration of the orphaned proteins into functional mature ribosomes that can start churning out proteins again. This rapid restart of ribosome production allows the cell to pick back up where it left off without wasting energy. The study also shows that cells unable to maintain the liquid state of these condensates don't recover as quickly, falling behind by ten generations while they try to reproduce the lost proteins. Asif developed an entirely new cell biological technique that lets researchers visualize orphaned ribosomal proteins in cells in real time, for the first time.
Ribosomes are crucial machines inside the cytoplasm of all cells that read the genetic instructions on messenger RNA and build chains of amino acids that fold into proteins. Producing ribosomes to perform this process is energy intensive, so under conditions of stress like heat shock, it's one of the first things a cell shuts down to conserve energy. Since he wanted to focus on what was happening to just the orphaned proteins during heat shock, Ali also used a classic technique called "pulse labeling" with a modern twist: a special dye called a "HaloTag" to flag the newly synthesized orphan proteins. Using these combined imaging tools, the researchers saw that the orphaned proteins were collected into liquid-like droplets of material near the nucleolus (Pincus used the scientific term "loosely affiliated biomolecular goo"). These blobs were accompanied by molecular chaperones, proteins that usually assist the ribosomal production process by helping fold new proteins. In this case, the chaperones seemed to be "stirring" the collected proteins, keeping them in a liquid state and preventing them from clumping together.
In the future, Ali hopes to employ another imaging technique called cryo-electron tomography, an application using an electron microscope while cell samples are frozen to capture images of their interior components at an atomic level of resolution. Another advantage of this technique is that it allows researchers to capture 3D images inside the cell itself, as opposed to separating and preparing proteins for imaging. Using this new tool, the researchers want to peer inside the protein condensates to see if they are organized in a way that helps them easily disperse and resume activity once the heat shock subsides.