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Quality control of glycogen through direct ubiquitylation by RNF213

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  • Article
  • Published:
  • Katerina Naydenova1 nAff5,
  • Elsje G. Otten1,
  • Alexander Heatley  ORCID: orcid.org/0009-0004-0789-24671,
  • Agnes Moe2,
  • Leonie Anton  ORCID: orcid.org/0000-0003-0008-21412,
  • Lucía de los Reyes-Ramírez  ORCID: orcid.org/0000-0001-7880-11993,
  • Helen E. Jolin1,
  • Frederic Langevin1,
  • Michal Wiacek1,
  • Catarina Franco1,
  • Anne Bertolotti  ORCID: orcid.org/0000-0002-9185-05583,
  • Wanda Kukulski  ORCID: orcid.org/0000-0002-2778-39362,
  • Andrew N. J. McKenzie  ORCID: orcid.org/0000-0001-9757-25121 &
  • …
  • Felix Randow  ORCID: orcid.org/0000-0003-0694-53151,4 

Nature (2026) Cite this article

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Abstract

Quality control of biomolecules is vital for organismal health. While DNA repair and protein quality control are well understood, how cells monitor other important biomolecules such as glycogen remains ill-defined. The accumulation of aberrant, poorly branched glycogen into insoluble polyglucosan bodies causes severe disease1,2. Here, we discover autophagy of ubiquitylated aberrant glycogen as a previously unrecognized quality control mechanism safeguarding the brain from polyglucosan buildup. This mechanism depends on the E3 ubiquitin ligase RNF213. Mice lacking ligase activity in RNF213 accumulate polyglucosan in cerebellum, pons, and hippocampus. Using cells engineered to produce polyglucosan, we show that RNF213 selectively ubiquitylates abnormal glycogen. Cryo-EM analysis of RNF213 bound to glycogen-derived maltoheptaose revealed its CBM20 domain binds linear oligosaccharides. Disrupting carbohydrate binding results in gain of E3 ligase activity towards physiological glycogen, indicating the CBM20 domain limits RNF213 activity towards physiological glycogen. Epistasis analysis places RNF213 upstream of LUBAC, suggesting a hierarchical network of multiple E3 ligases surveying glycogen quality. Ubiquitylated polyglucosan recruits the autophagy receptors SQSTM1, TAX1BP1, and optineurin, thereby triggering uptake into autophagosomes. These findings identify RNF213 as a quality control factor preventing polyglucosan accumulation in astrocytes through direct ubiquitylation of polyglucosan, revealing an essential role for non-protein ubiquitylation in glycogen quality control.

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Author information

Author notes

  1. Katerina Naydenova

    Present address: Max Planck Institute of Molecular Physiology, Dortmund, Germany

Authors and Affiliations

  1. Protein and Nucleic Acid Chemistry Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK

    Matthew C. J. Yip, Katerina Naydenova, Elsje G. Otten, Alexander Heatley, Helen E. Jolin, Frederic Langevin, Michal Wiacek, Catarina Franco, Andrew N. J. McKenzie & Felix Randow

  2. Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland

    Agnes Moe, Leonie Anton & Wanda Kukulski

  3. Neurobiology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK

    Lucía de los Reyes-Ramírez & Anne Bertolotti

  4. Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

    Felix Randow

Authors

  1. Matthew C. J. Yip
  2. Katerina Naydenova
  3. Elsje G. Otten
  4. Alexander Heatley
  5. Agnes Moe
  6. Leonie Anton
  7. Lucía de los Reyes-Ramírez
  8. Helen E. Jolin
  9. Frederic Langevin
  10. Michal Wiacek
  11. Catarina Franco
  12. Anne Bertolotti
  13. Wanda Kukulski
  14. Andrew N. J. McKenzie
  15. Felix Randow

Corresponding author

Correspondence to Felix Randow.

Supplementary information

Supplementary Fig. 1 (download PDF )

Source gel data for the cropped gels shown in the main Figures and Extended Data Figures.

Reporting Summary (download PDF )

Supplementary Fig. 2 (download TIF )

Gating strategy to distinguish lysosomal from cytosolic polyglucosan by flow cytometry. Samples were gated by FCS-A and SSC-A, followed by FSC-A and FSC-H gating, to identify cells and singlets, respectively. Subsequently, cells staining positive with the Cy5-labelled glycogen probe are gated, followed by analysis of Halo-TMR-labelling efficiency in glycogen-positive cells. As TMR labelling is inefficient in acidified autophagosomes, signal intensity per cell reflects the amount of cytosolic polyglucosan.

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Cite this article

Yip, M.C.J., Naydenova, K., Otten, E.G. et al. Quality control of glycogen through direct ubiquitylation by RNF213. Nature (2026). https://doi.org/10.1038/s41586-026-11139-6

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  • DOI: https://doi.org/10.1038/s41586-026-11139-6