GoKawiilQuality 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.
Quality control of glycogen through direct ubiquitylation by RNF213
Why This Matters
This research uncovers a previously unknown cellular quality control system that uses ubiquitylation—typically associated with protein regulation—to tag and clear abnormal glycogen before it accumulates into disease-causing polyglucosan bodies. The discovery expands the known scope of ubiquitin biology beyond proteins to carbohydrates, offering new insight into neurological disorders linked to glycogen storage defects and potential therapeutic targets.
Key Takeaways
- RNF213, an E3 ubiquitin ligase, directly tags abnormal glycogen for autophagic clearance, revealing a new non-protein ubiquitylation pathway.
- Loss of this ligase activity in mice causes toxic polyglucosan buildup in brain regions like the cerebellum and hippocampus, linking the mechanism to neurological disease.
- The study shows a coordinated network involving multiple E3 ligases and autophagy receptors (SQSTM1, TAX1BP1, optineurin) that maintains glycogen quality, opening new research avenues into metabolic and neurodegenerative disorders.
Explore topics:
rnf213
glycogen quality control
polyglucosan bodies
ubiquitylation
autophagy receptors
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