When we eat foods containing sugar, our bodies convert the excess into glycogen, where it is mainly stored in the liver and muscles.

For centuries, scientists have studied glycogen metabolism: a well-defined pathway taught to every biology and medical student across generations.

Professor David Komander, co-lead author on the study, said the team’s research added a new chapter to a book that had previously been considered complete.

“It’s quite likely biology books will need to be amended as a result of our findings,” Prof Komander, also head of WEHI’s Ubiquitin Signalling Division, said.

“We’ve uncovered a second pathway where glycogen can be directly regulated – likely on demand.

“This is an exciting breakthrough for people living with diseases caused by excessive glycogen.”

Glycogen Storage Diseases (GSD) are a group of rare inherited disorders that occur when the body can’t properly make or break down glycogen. They often remain without treatment options.

Excessive glycogen is also linked to more common conditions like diabetes, obesity, liver and heart disease.

These conditions are triggered by an accumulation of glycogen. To date, there are no therapies that can directly attack the glycogen molecule.

“Exciting new drugs – such as Ozempic – are transforming how we manage blood sugar, indirectly via hormonal regulation,” Prof Komander said.

“Without being able to regulate glycogen itself, it is hard to combat its accumulation – the root cause of many diseases.

“That’s why our study is exciting. We’ve found a way to go straight to the source.”

Ubiquitin is a protein that is well known to be attached to proteins, establishing a powerful control system, to help the body identify damaged proteins that need to be recycled or removed.

Glycogen is not a protein, but a sugar. And yet, this field-expanding study showed that ubiquitin can also attach to sugars, in animal models and human cells.

Co-lead author Dr Simon Cobbold said he was thrilled to see ubiquitin finally get its due credit.

“Ubiquitin is really an unsung hero that has been quietly working in the background all this time, keeping us alive,” Dr Cobbold said.

The breakthrough was made possible by NoPro-clipping, a cutting-edge technique that was developed by Dr Cobbold, Prof Komander and first author, Marco Jochem, over the past four years.

The pioneering technique enables researchers to study ubiquitin in unprecedented detail, and allows for the first time to detect non-protein ubiquitination events via mass spectrometry.

“Without our tools and method, this remarkable process would have remained invisible,” Dr Cobbold said.

“That’s the beauty of NoPro-clipping – it’s allowing us to study a canvas of molecules the ubiquitin field has overlooked all this time.”

PhD student Marco Jochem said the real strength of this tool lies in its versatility.

“Not only can we use it to detect ubiquitinated glycogen – we can also uncover ubiquitinated metabolites like glycerol and spermine, which we’ve discovered for the first time in all our cells,” he said.

“Our discovery is rewriting the fundamental rules of biology and ubiquitin signalling. And I’m sure we’ve only hit the tip of the iceberg.”

In the most striking part of the study, the researchers used NoPro-clipping to visualise how ubiquitin attached to glycogen inside the livers of mice when they were fed and fasted.

They found that when mice are in a fasting state and need energy, glycogen levels deplete.

Further, the presence of ubiquitin ‘tags’ increased during glycogen depletion, suggesting that sugar ubiquitination regulates glycogen breakdown.

The results show ubiquitin is a surprising new component in glycogen metabolism, adding a new layer to a well-understood ‘text-book’ biochemical process.

Importantly, the dynamic changes in sugar ubiquitin tags suggest a key control function that manages how and when glycogen is released.

The researchers were also able to increase ubiquitination of glycogen, which decreased glycogen in cells.

If these findings can be translated to animals and humans, new ways to tackle disease may be developed. Early discussions with investors are underway.

The study, “Ubiquitination of glycogen and metabolites in cells and tissues”, is published in Nature (DOI: 10.1038/s41586-026-10548-x). It is a collaboration between WEHI, The University of Melbourne, University of Cologne (Germany) and Alfred Health.

The research is supported by the National Health and Medical Research Council (NHMRC), National Institutes of Health (NIH) and Victorian Government.

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Header image: This image shows human liver cells treated with a drug that induces glycogen ubiquitination. The bright white speckles appear where glycogen and ubiquitin overlap, indicating that glycogen has been tagged with ubiquitin inside the cells.