Cellular "factories" ensure error-free protein folding

Folding helpers organize themselves into specialized units in our cells

Piecework: Biologists have discovered that small factories exist in our cells where amino acid chains are folded into functional proteins like an assembly line. According to the researchers, the already known helper proteins, which transform the newly produced proteins into their 3D form, are organized into previously unknown specialized units: droplet-like condensates. If these "factories" are missing, the folding helpers make more errors, and diseases such as diabetes develop, the team reports.

h, Model of PDIA6 chaperones condensates functioning as folding factories. source: Published: 11 August 2025 / A multichaperone condensate enhances protein folding in the endoplasmic reticulum / nature cell biology

Proteins perform a variety of functions in our cells: For example, they transport substances, assist in digestion as enzymes, and serve as building blocks. In order to fulfill these tasks, the amino acid chains produced in the cell's ribosomal protein factories must be arranged into their correct three-dimensional structure. The long chains must therefore be folded correctly.

What do chaperones do?

This protein folding is facilitated by an entire arsenal of helper proteins: the chaperones. These folding helpers are particularly numerous in the endoplasmic reticulum (ER) – the membrane structure inside the cell where most proteins are completed. Immediately after their "birth" in the ribosomes, the proteins are shaped by chaperones in the ER.

Researchers led by Anna Leder from the University of Basel have now examined one of these chaperones, PDIA6, in more detail. People with mutations in this helper protein often suffer from diseases, including liver fibrosis, diabetes, and neurodegenerative diseases. The team therefore conducted a series of experiments with different cell types to analyze exactly what this chaperone does and how this relates to the diseases.

Folding helpers on the assembly line

The biologists surprisingly discovered that PDIA6 and other chaperones in our cells assemble independently into specialized units. The driving force and basic framework is PDIA6. These molecules first interact with calcium ions, then with each other, and later numerous other chaperones join this structure.

"Traditionally, it was thought that the folding helpers float around individually in the ER," says Leder. "However, we discovered that they organize themselves independently and form droplet-like structures called condensates." These condensates represent small "folding factories" in which the helpers for protein folding are arranged like machines on an assembly line, the team explains.

This concentration of chaperones in a "factory" ensures a spatially and temporally efficient process and optimizes the function of the individual folding helpers. The condensates therefore increase the efficiency of protein folding and also serve as quality control. "The concentration of folding helpers is very high at this location, so unfolded or misfolded proteins are literally drawn in," explains Leder. "Only when they are correctly folded are they released."

Sickness due to a lack of folding factories

But what happens when PDIA6 is mutated and defective, preventing spontaneous folding factories from forming? While the individual chaperones continue to work on protein folding, they make more errors, as the tests have shown. This results in many unfolded or incorrectly folded proteins. This causes stress for the individual cells because they have to degrade and compensate for the unnecessary folds.

If this fails, harmful protein plaques or clumps build up. Furthermore, the body of those affected ultimately has too few fully folded and functional versions of certain proteins. One example is the hormone insulin, which regulates blood sugar. "The precursor pro-insulin is only properly folded within the condensates. In cells with mutations in the PDIA6 chaperone, these condensates do not form. They therefore produce less insulin and also secrete less of it," reports Leder.

Patients with PDIA6 mutations therefore suffer from, among other things, diabetes. But numerous other diseases are also linked to misfolded proteins, including neurodegenerative diseases, cystic fibrosis, and cancer.

Essential Unit

The team concludes that the newly discovered chaperone condensates do not just occur occasionally and randomly, but represent an essential organizational unit for our cells. "The functioning of the endoplasmic reticulum (ER) can probably only be explained and truly understood with the presence of condensates," says senior author Sebastian Hiller from the University of Basel.

With the knowledge of these "folding factories," previously known cellular processes can now be studied from a new perspective – which could ultimately benefit medicine and the treatment of diseases.

(Nature Cell Biology, 2025; doi: 10.1038/s41556-025-01730-w)

Source: University of Basel