Researchers led by Ludwig Maximilian University of Munich have mapped how ribosomes detect collisions during protein synthesis and activate a stress-response pathway via the kinase ZAK. By showing how ZAK recognizes stalled, collided ribosomes, the team’s Nature study highlights the role of the translation machinery in cellular surveillance and protection.
Ribosomes, best known for assembling proteins by reading messenger RNA (mRNA) and linking amino acids, also help monitor cellular health. When protein synthesis is disrupted by factors such as amino acid shortages, damaged mRNA or viral infection, translating ribosomes can stall and run into one another. According to Ludwig-Maximilians-Universität München, these collisions set off the ribotoxic stress response (RSR), which activates pathways that either repair the problem or, if the damage is too severe, lead to programmed cell death.
An international team led by Professor Roland Beckmann at LMU's Gene Center Munich used a combination of biochemical analyses and cryo-electron microscopy to dissect this mechanism.
The researchers showed that the kinase ZAK, a stress-response enzyme, is activated directly by collided ribosomes. They found that ZAK is recruited to these ribosome pairs and interacts with specific ribosomal proteins. These contacts cause defined regions of ZAK to dimerize – two copies of the protein pair up – which launches a downstream signaling cascade that activates protective cellular programs.
"A deeper understanding of these mechanisms is important for several reasons," Beckmann said, according to LMU. ZAK acts very early in the cellular stress response, so revealing how it recognizes ribosome collisions offers insight into how cells detect disturbances with high temporal precision. The work also helps clarify how ribosomal quality control connects to downstream signaling pathways and the immune response.
ZAK is of medical interest as well. Dysregulated ZAK activity has been linked to inflammatory diseases and chronic ribosomal stress, LMU notes. "Our findings thus illuminate a central principle of eukaryotic stress biology," Beckmann said. "The translation machinery itself serves here as a surveillance platform from which global stress signals are initiated."
The findings are reported in a Nature paper titled "ZAK activation at the collided ribosome" by Vienna L. Huso, Shuangshuang Niu, Marco A. Catipovic, James A. Saba, Timo Denk, Eugene Park, Jingdong Cheng, Otto Berninghausen, Thomas Becker, Rachel Green and Roland Beckmann. The article appears in Nature in 2025 under the DOI 10.1038/s41586-025-09772-8. Institutional summaries from LMU, ScienceDaily and Johns Hopkins Medicine attribute the work to a collaboration between LMU and Johns Hopkins and describe it as providing structural and mechanistic insight into how ribosome collisions trigger ZAK-dependent stress signaling.
