Ribosomes Serve as Stress Sensors in Cellular Function

Researchers at Ludwig Maximilian University of Munich have discovered that ribosomes, known primarily for their role in protein synthesis, also function as stress sensors within cells. Led by Professor Roland Beckmann from LMU's Gene Center Munich, the international team published their findings in the journal Nature.

Ribosomes read messenger RNA, or mRNA, to assemble proteins, but they also play a critical role in detecting cellular stress and initiating protective measures when faced with harmful conditions. When disruptions occur, such as limited amino acids, damaged mRNA, or viral infections, protein synthesis can falter, leading to ribosomes stalling and colliding with one another.

These collisions trigger a response known as the ribotoxic stress response, or RSR, which can activate pathways for damage repair or initiate programmed cell death if necessary. A key player in this process is the protein ZAK, a kinase that activates other molecules by transferring phosphate groups.

The research team utilized biochemical methods alongside cryo-electron microscopy to uncover how ZAK detects ribosome collisions and activates signaling pathways. They clarified that ZAK attaches to ribosomes, and specific structural features of the collided ribosomes are essential for its activation.

The findings revealed that ZAK interacts with particular ribosomal proteins, leading to dimerization, which is the pairing of two ZAK molecules. This dimerization sparks a cellular signaling cascade. Professor Beckmann emphasized the significance of understanding these mechanisms, particularly since ZAK operates at an early stage of the stress response.

Insights into how cells detect disturbances rapidly could enhance our understanding of ribosomal quality control, signaling networks, and immune responses. Moreover, abnormal ZAK activity has been linked to inflammatory diseases and ongoing ribosomal stress.

Beckmann stated, 'Our findings thus illuminate a central principle of eukaryotic stress biology,' highlighting the ribosome's dual role as both a protein-building machine and a surveillance platform for global stress signaling.

This research may pave the way for breakthroughs in cellular biology and disease treatments, by providing a deeper understanding of ribosomal function and stress responses.