Ubiquitination is appreciated as a pervasive modification of proteins to regulate their function and stability, and E3 ligases and DUBs have emerged as key players in all signalling pathways. Moreover, in the last few years cases of non-protein ubiquitination have surfaced, whereby ubiquitin molecules are attached to hydroxyl groups in glycans or lipids. In vitro, many E3 ligases can modify glycans, and functional deletion of a the E3 ligase HOIL-1 leads to abnormal glucagon deposits in cells. While it is currently unclear how pervasive and physiologically relevant sugar ubiquitination is, these studies suggest an emerging interplay of the ubiquitin system with energy metabolism at an unanticipated junction.
We have identified a new interactor of the LUBAC E3 ligase complex that includes HOIL-1, and have shown that it interacts with both ubiquitin and glycans. Deletion of the protein from mice leads to an obesity phenotype with liver pathology. In humans, the gene locus has undergone multiple duplication events since evolution from Neanderthals, suggesting roles in metabolism or nutrient uptake. We are trying to understand how the new adaptor links in with energy / glycan signalling pathways at the biochemical, structural and physiological level.
David Komander
Head, Ubiquitin Signalling Division, WEHI
Professor, Melbourne University
FAA