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In order to fulfill their many functions, proteins must be folded into the correct shape. Researchers at the University of Basel have now discovered tiny "folding factories" in cells that enable efficient and accurate protein folding. A lack of these structures can lead to diseases such as diabetes and neurodegenerative disorders.

Proteins are the workhorses of our cells: They transport substances, digest nutrients and serve as building blocks. To perform this wide range of tasks, they must be brought into the correct 3D structure, i.e. folded correctly. This process is ensured by an arsenal of folding assistants known as chaperones.

In collaboration with Professor Anne Spang, the team led by Professor Sebastian Hiller at the Biozentrum of the University of Basel, has now demonstrated that certain chaperones assemble into "folding factories" that guide newly synthesized, unfolded proteins into their correct shape.

The starting point for this research was a clinical observation: in several families with genetic diseases—including liver fibrosis, diabetes, and cognitive impairments—mutations were identified in a specific chaperone known as PDIA6. "This observation caught our attention," says Hiller. "We wanted to understand what PDIA6 actually does in the cell, so we began studying its function."

Folding factories in the cell

The endoplasmic reticulum (ER) is a cellular compartment dedicated to protein folding. It houses multiple chaperones for this purpose. "Traditionally, the folding helpers were thought to move around individually in the ER lumen," says Anna Leder, first author of the recently in Nature Cell Biology. "However, we found that chaperones self-organize into droplet-like structures called condensates."

These condensates work like conveyor belts, with optimally arranged folding machinery. The clustering of multiple different chaperones is initiated by PDIA6. PDIA6 molecules interact with each other to form a condensate, which then recruits other chaperones.

"Because of the high chaperone concentration in these condensates, unfolded or misfolded proteins are literally pulled in," says Leder. "Once the proteins folded properly, they are released from the folding factory." These condensates not only increase folding efficiency but also serve as a quality control system.

No insulin without condensates

But what happens when the folding factories are missing? The cells become severely stressed and, in the worst case, even die, as too many proteins remain unfolded or misfolded. The researchers confirmed this in follow-up experiments.

"We studied insulin, the hormone that regulates blood sugar," says Leder. "We found that its precursor, pro-insulin, is only folded correctly within these condensates. In cells with mutations in the PDIA6 chaperone, the condensates fail to form. As a result, the cells produce and secrete significantly less insulin."

These findings are consistent with clinical observations, where patients with PDIA6 mutations suffer from diabetes, among other conditions.

More than the sum of its parts

"This discovery is a real game-changer," emphasizes Hiller. Until now, such chaperone condensates were completely unknown. They are not just random by-products but important organizational units within the ER.

"We may need to rethink the concept of the ER, and possibly other cell organelles as well," says Hiller. "We cannot fully explain and understand ER function without considering the role of condensates."

The discovery of the self-organization of chaperones is important for future research and, in the long run, has implications for medical applications aimed at treating protein misfolding diseases such as neurodegenerative disorders, diabetes, cancer, and cystic fibrosis.