Scientists reveal a hidden alarm system inside your cells

Ribosomes are best known as the cell's protein builders. They attach to mRNA and travel along it, interpreting the genetic code and linking amino acids to form new proteins. Their role, however, extends beyond basic protein production. Ribosomes also help detect cellular stress and can trigger protective actions when the cell encounters harmful conditions. An international team led by Professor Roland Beckmann from LMU's Gene Center Munich has now identified the key steps that launch this stress signaling process. The results were published in Nature.

How Stress Disrupts Protein Production

Protein synthesis is extremely sensitive to disruptions such as limited amino acids, damaged mRNA, or viral infections. These forms of stress interfere with normal mRNA reading and can cause ribosomes to stall and run into one another. When collisions occur, they set off what is known as the ribotoxic stress response (RSR). This response activates pathways that either repair the damage or, if necessary, initiate programmed cell death.

Investigating ZAK With Biochemistry and Cryo-Electron Microscopy

The protein ZAK -- a so-called kinase, that is, an enzyme which activates other molecules by transferring a phosphate group to them -- plays a central role in controlling this stress response. Until now, it had been unclear how ZAK detects ribosomes that have collided and uses that information to activate signaling pathways. By combining biochemical experiments with cryo-electron microscopy, the research group demonstrated that ribosome collisions serve as the main activation cue for ZAK.

The scientists identified how ZAK attaches to ribosomes and which structural features of the collided ribosomes are necessary for its activation. They found that ZAK interacts with specific ribosomal proteins, causing particular regions of ZAK to dimerize, meaning that two copies of the protein pair up. This pairing initiates the cellular signaling cascade.

Why Understanding ZAK Matters

"A deeper understanding of these mechanisms is important for several reasons," says Beckmann. According to him, ZAK functions at one of the earliest stages of the stress response, so learning how it recognizes ribosome collisions offers valuable insight into how cells detect disturbances with remarkable speed. It also helps explain how ribosomal quality control, downstream signaling networks, and the immune system coordinate their responses.

ZAK is also of medical relevance, as abnormal ZAK activity is linked to inflammatory diseases and persistent ribosomal stress. "Our findings thus illuminate a central principle of eukaryotic stress biology," says Beckmann. "The translation machinery itself serves here as a surveillance platform from which global stress signals are initiated."