Summary
A Nature study identifies RNF213 as an enzyme that marks abnormal glycogen, or polyglucosan, for autophagy in brain cells. Experiments in engineered cells and mice link the pathway to protection against polyglucosan accumulation.
Cells have established systems for checking the quality of DNA and proteins, but how they monitor other biomolecules has been less clear. A study published in Nature on 15 September 2026 identifies one such system for glycogen: the enzyme RNF213 attaches ubiquitin to abnormal glycogen, directing it towards autophagy in brain cells.
Glycogen is a branched polymer made from glucose and is used for energy storage. When it is poorly branched, it can form insoluble deposits called polyglucosan bodies. The researchers describe RNF213 as a quality-control factor that helps prevent this material from accumulating in the brain.
Contents
How RNF213 identifies abnormal glycogen
RNF213 is an E3 ubiquitin ligase. These enzymes attach the small protein ubiquitin to selected targets, creating a signal that can alter the target’s handling by the cell. In this study, the target was not a protein but abnormal glycogen.
Using cells engineered to produce polyglucosan, the researchers found that RNF213 selectively ubiquitylated the abnormal material. The ubiquitin-labelled polyglucosan then recruited three autophagy receptors—SQSTM1, TAX1BP1 and optineurin. These receptors helped direct the material into autophagosomes, membrane-bound structures used by cells to isolate cargo for autophagy.
The researchers also used cryo-electron microscopy to examine RNF213 bound to maltoheptaose, a seven-sugar fragment derived from glycogen. The structure showed that RNF213’s CBM20 domain binds linear carbohydrate chains. This provides a molecular explanation for how the enzyme can recognise glycogen structures.
The CBM20 domain also acts as a control on the enzyme. When the researchers disrupted its carbohydrate-binding function, RNF213 gained activity against physiological glycogen—the normally structured form used by cells. The result indicates that CBM20 helps limit RNF213 activity so that ordinary glycogen is not treated like defective polyglucosan.
Evidence from cells and mice
The study combined biochemical and structural experiments with cell and animal models. In engineered cells, RNF213 selectively modified abnormal glycogen and initiated recruitment of autophagy machinery. An epistasis analysis placed RNF213 upstream of LUBAC, suggesting that glycogen surveillance involves a hierarchical network of more than one E3 ubiquitin ligase.
In mice lacking RNF213 ligase activity, polyglucosan accumulated in several brain regions, including the cerebellum, pons and hippocampus. The authors identify astrocytes as the brain cells in which RNF213 helps prevent this accumulation.
Together, these results connect the enzyme’s biochemical activity with tissue-level glycogen quality control: RNF213 recognises abnormal glycogen, labels it, and helps recruit the cellular machinery needed for its autophagic handling.
Why the finding matters
The work expands the known role of ubiquitylation beyond its better-known function in regulating proteins. It shows that a ubiquitin ligase can directly label a carbohydrate storage polymer and use that label to initiate autophagy.
That distinction is important because the buildup of poorly branched glycogen into polyglucosan bodies is associated with severe disease. The study provides a mechanism for how brain cells can distinguish abnormal glycogen from the physiological form and remove the defective material before it accumulates.
The evidence is from engineered cells, structural experiments and mice, rather than a human treatment study. The Nature article is an early-access version of peer-reviewed, accepted research and is marked for later replacement by a final Version of Record.