2026年4月22日出版的《自然》杂志发表了沃尔特和伊丽莎·霍尔医学研究所David Komander课题组的最新成果，他们开发出细胞和组织中糖原和代谢产物的泛素化。

课题组报告了非蛋白质剪接（NoPro-clipping）作为一种基于质谱的技术，结合了泛素剪接酶和分选酶标记。靶向和非靶向工作流程揭示了哺乳动物细胞、母细胞和人体组织中泛素修饰的巨大新画布。课题组在小鼠的任何含糖原的组织中发现泛素化糖原，在肝脏和骨骼肌中含量最高。泛素化可以将糖原运送到溶酶体，并导致糖原水平降低。糖原泛素化在糖原蓄积性疾病中受到调节，并受Met1-多泛素机制的调节。

引人注目的是，禁食期间肝脏中的糖原消耗与糖原泛素化升高相吻合，这表明泛素是生理糖原分解代谢的一个以前未知的成分。该研究团队还揭示了细胞和组织中内源性甘油和精胺的泛素化。因此，NoPro-clipping揭示了泛素化的意想不到的内源性非蛋白靶点，将泛素的作用从蛋白质修饰剂扩大到生物分子的一般修饰剂。

据悉，泛素信号传导覆盖了蛋白质修饰的广泛领域，但由于非蛋白质的底物，如糖、脂质和核苷酸，泛素信号传导仍可能被低估。泛素化的非蛋白底物的广度、丰度和细胞作用目前尚不清楚，因为目前的泛素组学和蛋白质组学技术对非蛋白修饰是盲目的。

附：英文原文

Title: Ubiquitination of glycogen and metabolites in cells and tissues

Author: Jochem, Marco, Cobbold, Simon A., Goodman, Craig A., Kueng, Catharina, Cerra, Anthony, Fielden, Laura F., Kim, Man Lyang, Schenk, Philipp, Agarwal, Ria, Wang, Xiangyi S., Scutts, Simon R., Pandos, Michael, Tang, Lin, Hermanns, Thomas, Devine, Shane M., Brzozowski, Martin, Shibata, Yuri, Geoghegan, Niall D., McLean, Catriona A., Lechtenberg, Bernhard C., Hofmann, Kay, Gregorevic, Paul, Komander, David

Issue&Volume: 2026-04-22

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.

DOI: 10.1038/s41586-026-10548-x

Source: https://www.nature.com/articles/s41586-026-10548-x