Subjects

- Homeostasis

- Metabolomics

- Proteomics

- Ubiquitylation

Abstract

Ubiquitin signalling covers a vast realm of protein modifications, yet may still be underestimated due to non-proteinaceous substrates, such as sugars, lipids, and nucleotides1 . The breadth of ubiquitinated non-protein substrates, their abundance, and cellular roles are currently unclear, since current ubiquitinomic and proteomic techniques are blind to non-proteinaceous modifications. We report Non-Protein Ub-clipping (NoPro-clipping) as a mass-spectrometry-based technique that combines ubiquitin clippases with sortase labelling. Targeted and untargeted workflows unveil a vast new canvas of ubiquitin modifications in mammalian cells, and in mouse and human tissues. We find ubiquitinated glycogen in any glycogen-containing tissue in mice, with highest abundance in liver and skeletal muscle. Ubiquitination can deliver glycogen to lysosomes, and leads to reduced glycogen levels. Glycogen ubiquitination is modulated in glycogen storage diseases and regulated by the Met1-polyubiquitin machinery. Strikingly, glycogen depletion in the liver during fasting coincides with elevated glycogen ubiquitination, suggesting that ubiquitin is a previously unknown component of physiological glycogen catabolism. We also reveal ubiquitination of endogenous glycerol and spermine in cells and tissues. NoPro-clipping hence unveils unexpected endogenous non-proteinaceous targets of ubiquitination, broadening the role of ubiquitin from a protein modifier to a general modifier of biomolecules.

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Author information

Author notes- These authors contributed equally: Marco Jochem, Simon A. Cobbold

Authors and Affiliations

- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

Marco Jochem, Simon A. Cobbold, Catharina Kueng, Anthony Cerra, Laura F. Fielden, Man Lyang Kim, Philipp Schenk, Ria Agarwal, Xiangyi S. Wang, Simon R. Scutts, Michael Pandos, Lin Tang, Shane M. Devine, Martin Brzozowski, Yuri Shibata, Niall D. Geoghegan, Bernhard C. Lechtenberg & David Komander

- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia

Marco Jochem, Simon A. Cobbold, Catharina Kueng, Anthony Cerra, Laura F. Fielden, Man Lyang Kim, Philipp Schenk, Xiangyi S. Wang, Simon R. Scutts, Michael Pandos, Lin Tang, Shane M. Devine, Martin Brzozowski, Yuri Shibata, Niall D. Geoghegan, Bernhard C. Lechtenberg & David Komander

- Centre for Muscle Research, Department of Anatomy and Physiology, University of Melbourne, Melbourne, VIC, Australia

Craig A. Goodman & Paul Gregorevic

- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia

Ria Agarwal

- Institute for Genetics, University of Cologne, Cologne, Germany

Thomas Hermanns & Kay Hofmann

- Department of Anatomical Pathology, AlfredHealth, Melbourne, VIC, Australia

Catriona A. McLean

Authors- Marco JochemView author publications