For cells to function properly, they must produce the right amount of each protein. It is a delicate balance: both too little and too much can compromise essential cellular functions. A team from the University of Geneva (UNIGE) has now shown that even a modest excess of tubulin – the protein that assembles into microtubules, the cell's internal scaffolding – is enough to disrupt tissue architecture and reduce cell viability. Published in Nature Communications, the study demonstrates that the quantity of a protein is just as important as its function.

Microtubules, built from tubulin, form the cell's internal skeleton. They help cells maintain their shape, transport molecules, divide, and remain firmly attached to neighbouring cells. Rather than being rigid structures, microtubules are constantly assembled and disassembled to adapt to the cell's changing needs. This dynamic behaviour depends directly on the amount of tubulin available.

For more than forty years, biologists have known that cells possess a mechanism that slows tubulin production when its levels become too high. However, the biological purpose of this regulatory pathway remained unknown. To address this question, the team led by Ivana Gasic, professor in the Department of Molecular and Cellular Biology at UNIGE's Faculty of Science, used three-dimensional spheroids. "These 3D cell culture models behave like tissues and reproduce cell-cell interactions much more faithfully than conventional two-dimensional cultures," she explains.

When a small excess becomes a big problem

Using advanced microscopy techniques, the researchers examined spheroids containing cells that produced 10-20% more tubulin than normal. "One might expect that having more of this protein would strengthen the cytoskeleton, but the opposite is true," says Ana Coelho de Almeida, postdoctoral researcher in Ivana Gasic's laboratory and first author of the study. "Excess tubulin makes microtubules abnormally stable and slows their ability to reorganise. As a result, cells can no longer adapt their architecture to the constraints of their environment."

The effects rapidly extend beyond individual cells. Proteins responsible for cell-cell adhesion and attachment to the extracellular matrix are no longer correctly positioned. Cell contacts weaken, tissue architecture progressively deteriorates, and cell viability declines. "Our findings show that cells regulate not only which proteins they produce, but also their abundance with remarkable precision. In the case of tubulin, even a slight excess is enough to disrupt tissue organisation. This reveals a fundamental principle of cellular biology," adds Ana Coelho de Almeida.

Beyond advancing the understanding of microtubule biology, the study establishes protein abundance control as a key mechanism for maintaining cellular homeostasis. This regulatory pathway is particularly relevant because microtubules are already targeted by several anticancer drugs, including paclitaxel, which stabilises microtubules to prevent tumour cells from dividing. In the future, a better understanding of this pathway could pave the way for new therapeutic strategies aimed at modulating tubulin levels or complementing existing treatments that target microtubule dynamics.