Protein condensates determine a cell’s fate

A cell can act in astonishingly complex ways. It must decide for itself whether to grow and multiply, rest, specialise, age or die. This applies just as much to mammalian cells as it does to seemingly simple microbes.

Cells take their cues not only from external signals but also from internal signals – such as their age or the amount of energy they have available. To ensure they have all the information they need, molecules from throughout a cell need to gather and form aggregates that can have different consistencies. They can be between liquid, gel-like, or solid. Scientists call these cellular information-gathering places “condensates.”

Clumps for decision-making

To date it has been unclear exactly how these condensates contribute to the cellular information exchange. Researchers at ETH Zurich led by biology professor Yves Barral have now discovered how this works in yeast cells. Their study has just been published in the journal Molecular Cell.

The researchers focused on cell aging to understand how these molecular clusters influence a yeast cell’s decisions. “As a cell can age independently of its environment, this is an ideal focus for our investigation,” explains Tom Peskett, a postdoctoral researcher in Barral’s group and first author of the study.

Two condensates must interact

Using microfluidics, which involves manipulating tiny amounts of fluid, he and his colleagues captured individual yeast cells. With the aid of a light microscope, the researchers observed how the cells divided and aged with each division, ultimately leading to their death three to four days later. The researchers observed that with increasing age, certain protein condensates – known as P-bodies and Whi3 condensates – formed inside the cells.

The researchers were able to show that the two condensates work together to stop the cell dividing when it becomes old. The condensates bind RNA molecules and suppress the production of the proteins involved in the cell division cycle. “If we disrupt one of the two condensates, the cells keep dividing well into old age,” explains Peskett.

To investigate the significance of the interaction between the condensates, the ETH biologists artificially triggered Whi3 condensates to form. This caused the cells to start aging earlier than usual. “This clearly shows that the aggregation of these proteins influences the cell's decision to retire and approach the end of its life,” says ETH professor Yves Barral. However, this only worked in cells containing both condensates, i.e. Whi3 condensates and P-bodies. “The interaction between the two condensates is crucial,” concludes Barral.

Active decision against mating

The condensates were also behind the cell’s decision to abort its mating attempts. Young yeast cells mate by sending signals to each other using specific pheromones. As soon as they detect each other, they decide not to divide anymore and instead form mating appendages that enable them to fuse with another yeast cell. Until today, researchers had assumed that old yeast cells were sterile and did not respond to pheromones from potential mating partners.

The ETH researchers have found that old cells do indeed respond to pheromones but very quickly abandon their mating attempts. “This decision is attributable to the condensates. If we prevent their formation, the old cells respond to pheromones in the same way as the young ones,” emphasises Barral.

Overall, these results show that this network of condensates controls two very different decisions: to end the cell cycle and to avoid mating in old age. “The condensates allow a cell to assess its age or the presence of potential mating partners and adjust its behaviour accordingly,” explains Barral.

The results also show that condensates and their interactions explain how molecules from across the cell come together to exchange crucial information. “It's as if they organise themselves into molecular committees that control the cell’s decisions,” adds Peskett.

Many cells make decisions that are detrimental to us as individuals – such as when cancer cells decide to multiply rapidly. Bacteria decide to go into a dormant state when they encounter antibiotics and wake up again to cause a recurrent infection. As we age, our stem cells stop producing new cells, with the result that injuries take more time to heal.

“The findings suggest a new approach to altering such decisions. However, further research is needed to develop drugs that specifically target condensates, allowing this knowledge to eventually be applied in a clinical setting,” stresses Barral.