Scientists Discover Ubiquitin Can Regulate Sugar, Challenging Long-Held Biological Assumptions

Australian researchers have identified a previously unknown mechanism by which the body controls stored sugar, revealing that ubiquitin—a molecule best known for tagging damaged proteins—can similarly directly interact with glycogen, a form of stored glucose. This discovery, led by scientists at the Walter and Eliza Hall Institute of Medical Research (WEHI), challenges decades of established understanding about how cellular processes are regulated and may open new avenues for treating metabolic diseases such as obesity, diabetes, and heart disease.

For years, biology textbooks have described glycogen metabolism as a two-step process: excess glucose is stored as glycogen in the liver and muscles, and when energy is needed, glycogen is broken down back into glucose. This system was considered well understood and stable. However, the WEHI team has uncovered a second, independent pathway that operates alongside the known mechanism.

“It’s quite likely biology books will need to be amended as a result of our findings,” said Professor David Komander, corresponding author of the study. “We’ve uncovered a second pathway where glycogen can be directly regulated—likely on demand.”

Ubiquitin Breaks Its Long-Standing Rule

Ubiquitin has long been recognized as a key player in cellular housekeeping. It functions by attaching to proteins and marking them for degradation, a process essential for maintaining cellular health. For decades, scientists believed ubiquitin’s activity was restricted to proteins only.

The new research shows that ubiquitin can also attach to glycogen, which is a polysaccharide—a sugar polymer—not a protein. This direct modification of glycogen by ubiquitin represents a fundamental shift in how scientists view the molecule’s capabilities.

“We’ve known about ubiquitin as a tag for proteins for decades,” Komander said. “But I’m still overwhelmed myself about what we have missed.”

A Novel Detection Tool Made the Discovery Possible

One reason this interaction went unnoticed for so long is the lack of tools capable of detecting ubiquitin’s activity on non-protein molecules like sugars, fats, or DNA. To overcome this limitation, Dr. Simon Cobbold and PhD student Marco Jochem, working in Komander’s lab, spent four years developing a specialized detection method to visualize and study ubiquitin’s interactions beyond proteins.

“Acting on a make-or-break hunch, Komander’s colleagues… spent four years inventing a way to reveal the action,” according to reports from the research team. This breakthrough tool allowed them to observe ubiquitin binding to glycogen in real time, confirming the existence of the new regulatory pathway.

Implications for Future Treatments

The discovery positions ubiquitin as a potential target for novel therapies aimed at regulating blood sugar more directly than current medications such as Ozempic, which work through hormonal pathways. By manipulating ubiquitin’s activity on glycogen, future treatments could offer more precise control over glucose storage and release.

Because ubiquitin is abundant in nearly all complex organisms—from humans to yeast—the mechanism is likely evolutionarily ancient and broadly conserved, increasing its relevance across species and disease contexts.

“The research throws the door open to a raft of new-to-science biological actions powered by the underestimated molecule,” Komander noted, emphasizing the wide-ranging implications of the finding.

Conclusion

This discovery marks a rare moment in modern biology where a core assumption about a fundamental cellular molecule is being revised. By demonstrating that ubiquitin can directly regulate glycogen, WEHI scientists have not only expanded the known functions of this ubiquitous molecule but also revealed a hidden layer of metabolic control that could one day transform how we treat metabolic disorders.

As research continues, the focus will shift to understanding how this pathway is regulated in health and disease—and whether targeting ubiquitin-glycogen interactions can safely and effectively improve outcomes for millions affected by sugar-related conditions.