MSc by Research: Sugar ubiquitylation, a new quality control mechanism for the recognition and elimination of unbranched glycogen?

The accumulation and precipitation of unbranched glycogen in human tissues as toxic polyglucosan bodies (PB) underlies four human diseases that cause cardiomyopathy and heart failure and/or fatal neurological disorders. They result from mutations in the genes encoding the E3 ubiquitin ligases HOIL-1 or Malin, or the Malin-interacting protein Laforin, or from deficiency of glycogen branching enzyme (GBE1) or the glycogen synthesis priming protein glycogenin-1 (GYG1).   

We discovered that HOIL-1 is an unusual E3 ligase that attaches ubiquitin to the hydroxyl side chains of serine and threonine residues in proteins https://www.pnas.org/doi/epdf/10.1073/pnas.1905873116 and to the C6 hydroxyl groups of glucose residues in unbranched glycogen https://doi.org/10.15252/embj.2021109700 . These and other observations led us to propose that the HOIL-1-catalysed monoubiquitylation of unbranched glycogen leads to its polyubiquitylation by the malin-laforin complex and perhaps other E3 ligases,  resulting in the elimination of the unwanted, toxic, unbranched glycogen by an autophagic mechanism  

Recently, we made demonstrated for the first time unbranched glycogen formed in GBE1 knockout (KO) human cells is polyubiquitylated, but normally branched glycogen formed in the parental wild type cells is not. The aim of the project is to investigate whether the abnormal glycogen formed in GYG1 KO cells is ubiquitylated and transported to lysosomes for destruction by lysosomal acid alpha 1:4 glucosidase by the same mechanism as the unbranched glycogen formed in GBE1 KO cells.  

The project will involve making GYG1 KO cells, HOIL-1/GYG1, Malin/GYG1 and Laforin/GYG1 double KO cells by CRISPR/Cas9 gene editing technology followed by isolation of the glycogen formed in these cells. The polyubiquitin chains attached to glycogen in GYG1 KO cells will be analysed to identify the different ubiquitin linkage types present, and compared to the ubiquitylated, unbranched glycogen formed in GBE1 KO cells. If time permits, the mechanism by which polyubiquitylated unbranched glycogen is transported to lysosomes will also be elucidated. These studies will help to establish whether every disease caused the accumulation and precipitation of PB (i.e. in patients deficient in HOIL-1, malin, laforin, GYG1 or GBE1) can be explained by a common underlying mechanism.  

The research challenges current dogma that ubiquitylation is confined to proteins, and promises to establish sugar ubiquitylation as new quality control mechanism for the elimination and hydrolysis of unwanted, toxic unbranched polysaccharides from cells 

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Life Sciences MSc by Research MSc by Research (Postgraduate) : Study : University of Dundee

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