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A ubiquitin ligase tags malformed glycogen for disposal in the mouse brain
Researchers at Cambridge and the MRC Laboratory of Molecular Biology report in Nature that the enzyme RNF213 ubiquitylates poorly branched glycogen directly, and that mice without that ligase activity accumulate polyglucosan in three brain regions.
The Scientist · Science desk
What happened
- Glycogen stays soluble because it is heavily branched, and when cells build it badly the sugar collapses into dense polyglucosan bodies that pile up inside brain cells and cause irreversible damage.
- A Nature paper from Cambridge and the MRC Laboratory of Molecular Biology reports that the enzyme RNF213 attaches ubiquitin directly to defective glycogen, which triggers autophagy to break it down.
- Mice whose RNF213 lacks ligase activity accumulated polyglucosan in the cerebellum, pons and hippocampus.
- Cryo-EM of RNF213 bound to glycogen-derived maltoheptaose showed that the enzyme's CBM20 domain binds linear oligosaccharides.
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Why it matters
- constraint A drug here would have to raise the activity of a destructive enzyme without aiming it at the glucose store cells depend on, and the one manipulation that raised activity in this study did exactly that.
- capability The study's flow cytometry separates polyglucosan already inside lysosomes from polyglucosan still in the cytosol. A screen for compounds that speed clearance now has something quantitative to read.
- precedent Ubiquitin has been treated as a tag on proteins. A sugar substrate makes it reasonable to go looking for other non-protein targets and the ligases that mark them.
The CBM20 domain works as a limit. When the authors disrupted its carbohydrate binding, RNF213 gained ligase activity toward physiological glycogen [6]. The domain that lets the enzyme recognise abnormal sugar is also what keeps it off the cell's working glucose store. Anyone designing an activator inherits that arrangement.
"A few years ago, we found RNF213 ubiquitylates LPS on intracellular bacteria, marking them for destruction. It is remarkable to see the same enzyme fighting bacteria and policing glycogen," said senior author Felix Randow, director of research at the University of Cambridge's Department of Medicine and a group leader at the MRC Laboratory of Molecular Biology [10].
RNF213 is not alone on the job. Epistasis analysis places it upstream of LUBAC, which the authors read as a hierarchical network of several E3 ligases surveying glycogen quality [7]. Downstream, ubiquitylated polyglucosan recruits the autophagy receptors SQSTM1, TAX1BP1 and optineurin, and the deposits are then taken up into autophagosomes [8]. The paper places this quality control in astrocytes [9].
The broader claim is about ubiquitin itself, which has been studied mainly as a regulator of proteins and is here shown labelling a carbohydrate directly [20]. "We are beginning to realize that ubiquitylation extends far beyond proteins. It is exciting to see what new biological roles emerge in the future," said first author Matthew Yip, a postdoc in the Protein and Nucleic Acid Chemistry Division of the MRC Laboratory of Molecular Biology [11].
The animal evidence comes from mice, and the abnormal sugar in the cell experiments came from cells engineered to produce polyglucosan [4]. The published abstract does not report a human carrying an RNF213 variant alongside disease. Cambridge names Lafora disease and polyglucosan body myopathy as the conditions this pathway speaks to [19].
Lafora disease was identified in 1911 by the Spanish neurologist Gonzalo Rodríguez Lafora [14], which is 115 years before this paper appeared [15]. It typically begins in adolescence and progresses through severe seizures, rapid cognitive decline and loss of motor control, and it is ultimately fatal [13]. It remains incurable, and existing options only manage symptoms [14].
What to watch
- Whether anyone reports human RNF213 loss-of-function variants in patients with polyglucosan body disease.
- Whether raising RNF213 activity in mice clears deposits that have already formed, and whether it spares normal glycogen.
- Whether LUBAC or another ligase in the hierarchy compensates when RNF213 ligase activity is removed.