Postdoctoral Research Vacancy, MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee.

Following an inaugural UKRI Pioneer Award to Sir Philip Cohen, applications are invited for a Postdoctoral Researcher to fill this position. The project will test the hypothesis that the ubiquitylation of unbranched glucosaccharides formed by errors of metabolism is a mechanism for eliminating these insoluble starch-like molecules before they precipitate in tissues, causing cardiomyopathy, heart failure and other diseases. The initial goal is to detect ubiquitylated unbranched glucosaccharides in cells by exploiting cell lines developed by the lab in which the formation of unbranched glucosaccharides has been accelerated and their elimination suppressed. The longer term goals are to elucidate the mechanism of glycophagy and to identify further examples of sugar ubiquitylation in biology.

Applicants must have a PhD and at least one 1st author paper published or accepted in a peer-reviewed journal. A strong background in biochemistry is essential and experience in one or more of the following is desirable:- protein chemistry, protein ubiquitylation, autophagy; glycogen metabolism. The position will be an opportunity for candidates to broaden their skillset by working in a well-funded lab using state-of-the-art technologies.

For further information about this position please contact Philip Cohen (p.cohen@dundee.ac.uk). To find out more about the MRC Protein Phosphorylation and Ubiquitylation Unit please visit https://www.ppu.mrc.ac.uk.

The closing date for applications is February 29th 2024. The successful applicant will receive a fixed term contract of one year which can start at any time up to July 1st 2024

Background - Sugar ubiquitylation; a new surveillance mechanism for the recognition and elimination of misfolded macromolecules?

Human HOIL-1 deficiency leads to the accumulation of unbranched glucosaccharides in muscles and other tissues that lack the alpha1:6 branch points present in normally branched glycogen. These molecules precipitate in cells as insoluble deposits termed Polyglucosan Bodies (PB), causing cardiomyopathy and heart failure in young adults. We discovered that HOIL-1 is an atypical E3 ubiquitin ligase that ubiquitylates the hydroxyl side chains of serine and threonine residues in proteins forming ester bonds (Kelsall et al, 2019, Proc Natl. Acad Sci USA mice 116, 13293-13298). More recently, we found that mice in which HOIL-1 had been replaced by an E3-ligase inactive mutant accumulate PB in the heart, brain and other tissues. We also found HOIL-1 can ubiquitylate unbranched glucosaccharides at the C6 hydroxyl group of glucose in vitro and that the ubiquitylation of this sugar was greatly enhanced by HOIP (HOIL-1-interacting protein) (Kelsall et al, 2022, EMBO J. 41:e109700). These findings led us to propose the hypothesis that one of the roles of HOIL-1 in mammalian cells is to ubiquitylate unbranched glucosaccharides formed by errors of metabolism, marking them for elimination by glycophagy, a process analogous to autophagy in which the ubiquitylated glucosaccharides are taken up into lysosomes where they are hydrolysed by the lysosomal alpha1:4 glucosidase, before they precipitate in the cytosol as toxic PB. The aim of the project is to establish whether this hypothesis is correct, which would establish sugar ubiquitylation as a novel quality control mechanism and open-up a new aspect of ubiquitin biology.