Colliding ribosomes signal cellular stress

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Ribosomes, the protein factories of the cell, are essential for all living organisms. They bind to mRNA and move along the messenger molecule, reading the genetic code as they go. Using this information, they link amino acids to make proteins. But their function goes far beyond pure production: Ribosomes are also important sensors for cellular stress and initiate protective reactions when problems arise. An international team led by Professor Roland Beckmann from LMU’s Gene Center Munich has identified key mechanisms behind the triggering of this stress response. The researchers set out their findings in the journal Nature.

Protein production in cells reacts very sensitively to numerous stresses, including amino acid deficiency, mRNA damage, and viral infections. Such stressors impair the reading of mRNA and can lead to ribosomes stalling and colliding with each other. This sets in motion the so-called ribotoxic stress response (RSR), which activates protective programs whereby the damage is either removed or cell death is initiated.

Combination of 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 key role in mediating the stress response. Scientists were unsure how ZAK recognizes collided ribosomes and thus triggers the stress response. Through the combination of biochemical analyses and cryo-electron microscopy, the research team has demonstrated that ribosome collisions are in fact the primary activation signal of ZAK. The researchers showed how ZAK is recruited to the ribosomes and which structural features of collided ribosomes ZAK must recognize in order to be activated: Interactions between ZAK and certain ribosomal proteins cause special areas of ZAK to dimerize, which is to say, join together to form a bonded pair. This sets the signal cascade in motion.

“A deeper understanding of these mechanisms is important for several reasons,” says Beckmann: First of all, ZAK acts very early in the cellular stress response, and so clarifying its recognition mechanisms furnishes important insights into how cells perceive disturbances with high temporal precision and how ribosomal quality control, downstream signaling pathways, and the immune response interact with each other. Furthermore, ZAK is therapeutically relevant, as dysregulated ZAK activity is associated with inflammatory diseases and chronic 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.”

V.L. Huso et al.: ZAK Activation at the Collided Ribosome. Nature 2025