Adaptive energetic tuning of nucleolar phase separation regulates rRNA transport

Eukaryotic cells modify their biochemical pathways in reaction to environmental stress, temporarily suspending energy-intensive processes such as protein synthesis and ribosome biogenesis. Ribosome production takes place within a complex, multi-phase structure known as the nucleolus, which is divided into three sections associated with rRNA transcription, processing, and assembly.

While drugs and light-activated methods that create a gel-like structure within the nucleolus can disrupt its stability and obstruct ribosome production, it is still not clear if the nucleolus' properties are actively altered in response to metabolic and growth cues.

In this study, researchers explored how nucleolar phase separation is adapted to the body's requirements. By observing endogenously tagged NPM1 in live cells, they found a strong correlation between NPM1 distribution and the availability of nutrients. When the body is lacking in nutrients, NPM1 concentrations in the nucleolus rise, suggesting that the phase separation becomes more stable and gel-like.

Consequently, rRNA diffusion slows down, and the nucleolar meshwork tightens. This alteration is accompanied by a decrease in rRNA processing, implying that diminished transport capabilities prevent immature ribosome subunits from exiting the nucleolus. Mechanistically, these changes are driven by ATP levels, which significantly impact the energy-demanding process of ribosome biogenesis.

When ATP levels are restored following the reintroduction of nutrients, the nucleolus reverts to its normal composition within minutes, indicating that the process is actively regulated. In summary, these findings indicate that the nucleolus' physical properties are not static but are dynamically modified by cellular energy levels, linking phase separation dynamics to the metabolic control of ribosome biogenesis.