A ribosome assembly stress response regulates transcription to maintain proteome homeostasis

When yeast cells are growing at top speed, they can make 2,000 new ribosomes every minute. These enormous molecular assemblies are the protein-making machines of the cell. Building new ribosomes is one of the most energy-demanding parts of cell growth and, if the process goes wrong, the results can be catastrophic. The proteins that make up the ribosomes themselves are sticky. Left unattended, they start to form toxic clumps inside the compartment that houses most of the cell’s DNA, the nucleus. A protein called Heat shock factor 1, or Hsf1 for short, plays an important role in the cell's quality control systems. It helps to manage sticky proteins by switching on genes that break down protein clumps and prevent new clumps from forming. Hsf1 levels start to rise whenever cells are struggling to keep up with protein production. If it is half-finished ribosomes that are causing the problem, cells can stop making ribosome proteins. The protein in charge of this in yeast is Ifh1. It is a transcription factor that sits at the front of the genes for ribosome proteins, switching them on. When yeast cells get stressed, Ifh1 drops away from the genes within minutes, switching them off again. Yet how this happens, and how it links to Hsf1, is a mystery. To start to provide some answers, Albert et al. disrupted the production of ribosomes in yeast cells and examined the consequences. This revealed a new rescue response, that they named the “ribosome assembly stress response”. Both Hsf1 and Ifh1 are sensitive to the build-up of unfinished ribosomes in the nucleus. As expected, Hsf1 activated when ribosome proteins started to build up, and switched on the genes needed to manage the protein clumps. The effect on Isfh1, however, was unexpected. When the unassembled ribosome proteins started to build up, it was the clumps themselves that pulled the Ifh1 proteins off the genes. The unassembled ribosomes proteins seemed to be stopping their own production. Low levels of clumped ribosome proteins in the nuclei of unstressed cells also helped to keep Hsf1 active and pull Ifh1 off the ribosome genes. It is possible that this provides continual protection against a toxic protein build-up. These findings are not only important for understanding yeast cells; cancer cells also need to produce ribosomes at a very high rate to sustain their rapid growth. They too might be prone to stresses that interrupt their ribosome assembly. As such, understanding more about this process could one day lead to new therapies to target cancer cells.