Ribosomes in pairs

Scientists discover RNA-driven mechanism that helps neurons endure prolonged starvation

To the Point

• Ribosomes: Scientists found that stressed neurons pair inactive ribosomes into structures called disomes to survive starvation. This discovery reveals a new way cells manage protein production during stress.
• RNA Mechanism: The connection between ribosomes is made by an RNA segment, not proteins, highlighting the role of ribosomal RNA in cellular stress responses.
• Implications: This research enhances our understanding of how cells adapt to stress and the importance of ribosome organization in health and disease.

Ribosomes are large molecular machines made of protein and RNA that build all proteins in the cell. Because protein production is extremely energy-intensive, cells rapidly reduce protein synthesis when stressed. It has long been known that bacterial cells pair their inactive ribosomes into so-called “hibernating disomes” however, such structures had not previously been identified in animal cells.

Using advanced imaging techniques, Erin Schuman and her team at the Department of Synaptic Plasticity at the Max Planck Institute for Brain Research in Frankfurt discovered that stressed animal cells - including neurons - assemble inactive ribosomes into tightly linked pairs, known as disomes. These ribosome pairs are not accidental collisions or artifacts, but a regulated and reversible response to stress. The new study was published today in Science.

“Surprisingly, the two ribosomes are not held together by proteins, as is common in bacteria. Instead, the connection is made by a specific piece of ribosomal RNA called an expansion segment”, explains one of the lead authors, postdoctoral researcher, Andre Schwarz.

Expansion segments are long, flexible RNA “tentacles” that protrude from ribosomes and have grown larger over the course of evolution. Although they are a prominent feature of animal ribosomes, their functions only just started to emerge. This study now shows that one particular expansion segment, called “31b”, is both necessary and sufficient to link ribosomes together during stress. At the molecular level, the expansion segment forms a precise RNA-RNA interaction - a so-called “kissing loop” - in which identical RNA loops bind each other through complementary sequences. Disrupting this interaction prevents disome formation, stunts cellular growth and makes cells more sensitive to stress.

Seeing ribosomes inside cells

A key strength of the study was the ability to visualize ribosomes directly inside intact cells using cryogenic electron tomography (Cryo-ET). Cryo-ET is a powerful 3D imaging technique that uses an electron microscope to see inside frozen biological samples (cells, organelles, molecules) with very high resolution. This approach allowed the team to visualize ribosomes in their native environment and resolve how they re-organize during stress.

The study combined an unusually broad range of techniques, including cell biology, biochemistry, yeast and mammalian cell genetic engineering, and high-resolution structural imaging. “One major challenge was manipulating ribosomal RNA, which is encoded by hundreds to thousands of nearly identical gene copies in animal genomes. We overcame this hurdle by engineering hybrid ribosomes in yeast and by introducing small RNA molecules that specifically disrupted ribosome pairing in animal cells”, says Mara Mueller, graduate student in the Schuman Lab and co-first author of the study.

A new view of translation control

„Our findings uncover a previously unknown mechanism by which animal cells regulate protein synthesis during stress - one that relies on RNA structure. The study reveals a new function for ribosomal RNA expansion segments which have been rather mysterious”, says Erin Schuman.

By temporarily storing ribosomes in inactive pairs, cells protect these costly machines and enable rapid recovery once favorable conditions return. The discovery opens new avenues for understanding how cells adapt to stress and how ribosome organization contributes to health and disease.