Our understanding of how cells handle stress is changing. New research published in Molecular Cell from the Zaher Lab sheds light on Mbf1, an important protein that works as a sensor, challenging previously held beliefs about cellular stress responses.
When the going gets tough, the Integrated Stress Response (ISR) helps cells adapt to stressful situations. One of its key strategies is to stop global protein production: “Protein synthesis is very expensive, energetically,” Hani Zaher, professor of biology and corresponding author, explained. “If you’re under stress, you don’t want to be wasting energy making proteins that might not help you deal with it.” At the same time, cells must make certain proteins to survive and recover from the stress. In yeast, a protein called Mbf1 is central to this ISR process. Mbf1 was originally thought to directly aid the ISR by helping its key effector protein, Gcn4, to turn the survival genes on.
However, Zaher and his team, together with their collaborators, found that Mbf1 helps in a completely different way—it’s in charge of monitoring the ribosomes. The ribosomes make protein, moving along the mRNA as they go, but sometimes, when conditions are stressful, these ribosomes pile up. A ribosome traffic jam. Mbf1 acts like an alarm system in this scenario, attaching itself to the collided ribosomes and alerting another protein, Gcn2, to halt protein production. “If you think about this being a highway, when the cars—the ribosomes—collide, the first thing that needs to be done is to block all of the ramps leading to the highway because you don’t want more collisions,” Zaher said. In short, Mbf1 is the first protein on the scene—the one that calls in the emergency services.
Though this study focused on Mbf1 in yeast, this protein has a homologue in humans—EDF1. “Mbf1 is conserved in eukaryotes, it is even found in Archaea where it also binds ribosomes. The only place it appears not to be found is in bacteria,” Zaher said. No matter where the protein is tested, including plants, it appears to be important for stress response.
In other words, these findings help us understand how a multitude of eukaryotes may respond to stress. Looking forward, the Zaher Lab is hoping to take a closer look at how these stress responses are conserved across different organisms.
