WEHI researchers have discovered a never-before-seen mechanism our bodies use to regulate sugar, in findings that rewrite the fundamental rules of biology and open a new frontier in science.<\/p>\n
Published in\u00a0Nature, the study is the first to uncover a potential therapeutic process that could be used to directly reduce the amount of sugar stored in the body. \u00a0<\/p>\n
The findings could have clinical implications for people living with conditions caused by excessive sugar levels, including diabetes, heart disease, and a set of rare disorders that currently have no treatment\u00a0options.<\/p>\n
At a glance<\/b><\/p>\n
WEHI researchers have discovered that stored sugar (glycogen) can be directly regulated using ubiquitin \u2013 a critical protein that \u2018tags\u2019 damaged proteins for recycling or removal.TheNaturestudy is the first to show ubiquitin can regulate glycogen in humans,overturning 50 years of scientific knowledge.The findings, made possible by a pioneering new method developed by the team, could pave the way for new treatments for diseases caused by abnormal sugar storage, including heart and liver disease, and for people with rare Glycogen Storage Diseases.<\/p>\n
When we eat foods containing sugar, our bodies convert the excess into glycogen, where it is mainly stored in the liver and muscles.<\/p>\n
For centuries, scientists have studied glycogen metabolism: a well-defined pathway\u00a0taught to every\u00a0biology and medical student across generations.<\/p>\n
Professor David Komander, co-lead author on the study, said the team\u2019s research added a new chapter to a book that had previously been considered complete.<\/p>\n
\u201cIt\u2019s quite likely biology books will need to be amended as a result of our findings,\u201d Prof Komander, also head of WEHI\u2019s\u00a0Ubiquitin Signalling Division<\/a>,\u00a0said.<\/p>\n \u201cWe\u2019ve uncovered a second pathway where glycogen can be directly regulated \u2013 likely on demand.<\/p>\n \u201cThis is an exciting breakthrough for people living with diseases caused by excessive glycogen.\u201d<\/p>\n Glycogen Storage Diseases (GSD) are a group of rare inherited disorders that occur when the body can\u2019t properly make or break down glycogen. They often remain without treatment options.Excessive glycogen is also linked to more common conditions\u00a0like diabetes, obesity, liver and heart disease.<\/p>\n These conditions are triggered by an accumulation of glycogen. To date, there are no therapies that can directly attack the glycogen molecule. \u00a0<\/p>\n \u201cExciting new drugs \u2013 such as\u00a0Ozempic \u2013 are transforming how we manage blood sugar, indirectly via hormonal regulation,\u201d Prof Komander said.<\/p>\n \u201cWithout being able to regulate glycogen itself, it is hard to combat its accumulation \u2013 the root cause of many diseases.<\/p>\n \u201cThat\u2019s why our study is exciting. We\u2019ve found a way to go straight to the source.\u201d<\/p>\n The hidden hero<\/b><\/p>\n 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.\u00a0<\/p>\n 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.<\/p>\n Co-lead author Dr Simon Cobbold said he was thrilled to see ubiquitin finally get its due credit.<\/p>\n \u201cUbiquitin is really an unsung hero that has been quietly working in the background all this time, keeping us alive,\u201d Dr Cobbold said.<\/p>\n 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.<\/p>\n The pioneering technique enables researchers to study ubiquitin in unprecedented detail, and allows for the first time to detect non-protein ubiquitination events via\u00a0mass spectrometry<\/a>.<\/p>\n \u201cWithout our tools and method, this remarkable process would have remained invisible,\u201d Dr Cobbold said.<\/p>\n \u201cThat\u2019s the beauty of NoPro-clipping \u2013 it\u2019s allowing us to study a canvas of molecules the ubiquitin field has overlooked all this time.\u201d<\/p>\n PhD student Marco Jochem said the real strength of this tool lies in its versatility.<\/p>\n \u201cNot only can we use it to detect ubiquitinated glycogen \u2013 we can also uncover ubiquitinated metabolites like glycerol and spermine, which we\u2019ve discovered for the first time in all our cells,\u201d he said.<\/p>\n \u201cOur discovery is rewriting the fundamental rules of biology and ubiquitin signalling. And I\u2019m sure we\u2019ve only hit the tip of the iceberg.\u201d<\/p>\n Fast results \u2013 how the study was conducted\u00a0<\/p>\n 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.<\/p>\n They found that when mice are in a fasting state and need energy, glycogen levels deplete.Further, the presence of ubiquitin \u2018tags\u2019 increased during glycogen depletion, suggesting that sugar ubiquination regulates glycogen breakdown.<\/p>\n The results show ubiquitin is a surprising new component in glycogen metabolism, adding a new layer to a well-understood \u2018textbook\u2019 biochemical process.<\/p>\n Importantly, the dynamic changes in sugar ubiquitin tags suggest a key control function that manages how and when glycogen is released.<\/p>\n The researchers were also able to increase ubiquitination of glycogen, which decreased glycogen in cells.<\/p>\n If these findings can be translated to animals and humans, new ways to tackle disease may be developed. Early discussions with investors are underway.\u00a0<\/p>\n The study, \u201cUbiquitination of glycogen and metabolites in cells and tissues\u201d, is published in\u00a0Nature<\/a>.\u00a0It is a collaboration between WEHI, The University of Melbourne, University of Cologne (Germany) and Alfred Health.<\/p>\n The research is supported by the National Health and Medical Research Council (NHMRC), National Institutes of Health (NIH) and Victorian Government<\/p>\n