Australian researchers claim that ‘biology books will need to be amended’ after discovering glycogen can be directly regulated by ubiquitin.
For decades it was believed that there was only one way our bodies converted excess sugar to glycogen before storing it in places such as the liver and muscles.
But now, Australian researchers have developed a never-before-seen mass spectrometry-based approach that allowed them to identify and directly target glycogen stored in the body.
The new technique, called non-protein ubiquitin-clipping (NoPro-clipping), takes advantage of ubiquitin’s role in helping the body identify damaged proteins for removal – and the fact that ubiquitin can attach to glycogen molecules despite it not being a protein.
“The work presented here unveils a new layer of ubiquitin biology, which we access via a new mass-spectrometry workflow,” the researchers wrote in Nature. “We discover a surprisingly high abundance and diversity of non-proteinaceous material ubiquitinated in cells.”
“Key enzymes in method development are Ub-clippases and sortase, which when used together enable selective peptide labelling of clippase products. Our method relies on the breakdown of ubiquitinated macromolecules into small molecule, metabolite-like species.
“We were surprised to discover high amounts of ubiquitin attached to glucose within glycogen, which we detected by NoPro-clipping, in any glycogen-containing tissue analysed from mice. The most striking data suggest that during fasting, while glycogen is actively depleted, the amount of ubiquitinated glycogen increases, indicating that ubiquitin responds to metabolic cues and partakes in glycogen breakdown.”
Dr Simon Cobbold, co-lead author of the paper, said this process would have remained undiscovered if not for the NoPro-clipping approach. “Ubiquitin is really an unsung hero that has been quietly working in the background all this time, keeping us alive,” he said in a statement.
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Experiments in mice displayed that the number of ubiquitin ‘tags’ increases during times of glycogen depletion, such as fasting, and that increasing the ubiquitination of glycogen when levels were high decreased glycogen levels, highlighting ubiquitin as a “surprising new component” of glycogen metabolism.
Professor David Komander, co-lead author of the research and head of WEHI’s Ubiquitin Signalling Division, said the discovery was an “exciting breakthrough” for people affected by diabetes, obesity, liver and heart diseases and glycogen storage disorders.
“Exciting new drugs – such as Ozempic – are transforming how we manage blood sugar, indirectly via hormonal regulation,” he said in a statement. “[But] 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.”
The research team, who are in early discussions with potential investors regarding the newly developed technique, believe the approach could be applied to other metabolites.
