Ubiquitination of glycogen and metabolites in cells and tissues
Year: 2026
Type: article
Abstract: . The breadth of ubiquitinated non-protein substrates, their abundance and their cellular roles are currently unclear, as current ubiquitinomic and proteomic techniques do not detect non-proteinaceous modifications. Here we report non-protein ubiquitin clipping (NoPro-clipping) as a mass spectrometry-based technique that combines ubiquitin clippases with sortase labelling. Targeted and untargeted workflows unveil a wide range of ubiquitinated substrates in mammalian cells and in mouse and human tissues. We find ubiquitinated glycogen in glycogen-containing tissues in mice, with the highest abundance in liver and skeletal muscle. Ubiquitination can deliver glycogen to lysosomes and leads to decreased glycogen levels. Glycogen ubiquitination is modulated in glycogen storage diseases and is regulated by the Met1-polyubiquitin machinery. Notably, glycogen depletion in the liver during fasting coincides with increased 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 thus reveals unexpected endogenous non-proteinaceous targets of ubiquitination, broadening the role of ubiquitin from a protein modifier to a general modifier of biomolecules.
Source: Nature
Authors: Marco Jochem, Simon A. Cobbold, Craig A. Goodman, Catharina Kueng, Anthony Cerra, Laura F. Fielden, Man Lyang Kim, Philipp Schenk, Ria Agarwal, Xiangyi S. Wang, Simon R. Scutts, Michael Pandos, Lin Tang, Thomas Hermanns, Shane M. Devine, Martin Brzozowski, Yuri Shibata, Niall D. Geoghegan, Catriona A. McLean, Bernhard C. Lechtenberg, Kay Hofmann, Paul Gregorevic, David Komander
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Awards: G3773015375, IRIISS, G8603342924
OpenAlex ID: W7155171952