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February 24, 2021

from the Max Planck Institute for Immunobiology and Epigenetics

The transition from unicellular to multicellular organisms was an important step in the development of complex life forms. Multicellular organisms formed hundreds of millions of years ago, but the forces that underlie this event remain a mystery. To investigate the origins of multicellularity, Erika Pearce’s group at the MPI for Immunobiology and Epigenetics in Freiburg turned to the slime mold Dictyostelium discoideum, which can exist in both a unicellular and multicellular state and is at the forefront of this important evolutionary step. These dramatically different states depend on only one thing – the food.

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A key question from Pearce’s laboratory is the answer to the question of how changes in metabolism affect cell function and differentiation. Usually they examine immune cells to answer this question. However, when first author Beth Kelly joined the group, they decided to shift the focus. “We thought if we were interested in how nutrient availability causes changes in how cells work, there would be no better organism than Dicty, where hunger causes cells to go from their own state to a multicellular organism. This is.” immense shift in biology, “said Erika Pearce.

By simply depriving D. discoideum of its food supply, they could transform this organism from individual cells into a multicellular aggregate and thus study the factors that drive this multicellularity. The aggregate behaves like a complex, multicellular organism in which individual cells are specialized to have different functions and to move as a whole. Multicellular D. discoideum eventually forms a protective spore that enables the population to survive hunger.

Starvation of D. discoideum induced a rapid onset of reactive oxygen species (ROS) production. ROS are small molecules that are made by our cells, but were also used for signal transmission at the beginning of evolution, before more complex receptor-based systems existed. However, if the ROS levels are too high, they become harmful, oxidizing proteins and nucleic acids, and ultimately leading to cell death. So an increase in ROS is generally associated with the production of antioxidants to control this ROS. Beth Kelly remarked: “In our case, the production of the antioxidant glutathione increased to counteract the massive ROS outbreak when starving. If we gave the starving slime mold additional glutathione, we were able to block this increase in ROS and, above all, stop the formation of the multicellular one Aggregate, which keeps the cells in a unicellular state. “

When they again blocked glutathione production using an inhibitor, they found that, instead of promoting even faster aggregation, it reversed it and made the unicellular state longer maintained. This suggested that a function of supplemented glutathione other than antioxidant activity reversed the aggregation process. They thought carefully about how glutathione is made. It consists of only three amino acids, cysteine, glycine and glutamine. Kelly added each of these components individually back to starving cells and found that only cysteine ​​alone can reverse the multicellular aggregation of starvation.

What is unique about cysteine ​​biology? It is one of only two amino acids that contain sulfur, and this sulfur is critical to a wide variety of processes in proliferating cells. It is used to make new proteins, is essential for enzyme activity and supports metabolic processes for energy production. Limiting cysteine ​​therefore limits the supply of sulfur, slows growth and proliferation, and indicates that there are not enough nutrients to continue these processes. For Dictyostelium, this means that they should go into a multicellular state in order to form a spore that can survive this time of nutrient limitation and sustain the population.

It turned out that sulfur loss was the important process that underlying this multicellularity, and that increasing the ROS for D. discoideum was a smart way of achieving this goal. Thus, by increasing the ROS, starvation of dictyostelium increases glutathione production. “This actually pulls cysteine ​​into the cells in glutathione and limits the use of its sulfur for proliferation and protein production. By artificially blocking glutathione production or by providing extra cysteine ​​to the starving cells, we could restore that sulfur supply, restore proliferation and the unicellular state “said Beth Kelly. “We have shown how sulfur dictates a change between a unicellular and multicellular state.” Sulfur and oxygen were widespread in ancient times, small elements, and this work shows how they may have played a role in the development of multicellularity.

“Furthermore, we believe that our work has therapeutic effects on more complex organisms “Cancer cells are highly proliferative and some cancer cells specifically maintain sulfur metabolism. Restricting or controlling sulfur metabolic processes in these cells can improve anti-tumor immunity,” said Pearce. The movement of immune cells through environments with different nutrient mixtures and the function of the immune cells depend on the activity of the metabolic pathway. Manipulating sulfur metabolism can be a means of modulating the function of immune cells. Overall, the investigation of such conserved nutrient signaling pathways in the early eukaryote Dictyostelium will likely be very informative for the function of mammalian cells.

The study is published in Nature.

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