The Linear Ubiquitin Assembly Complex (LUBAC) contains two E3 ubiquitin ligases, called HOIP and HOIL-1. HOIP catalyses the formation of Met1-linked ubiquitin (also called linear ubiquitin) chains, which are required to activate the IkB kinase (IKK) complex that switches on the master transcription factors of the innate immune system, NF-kB and IRF5 (interferon regulatory factor 5). In contrast, we have recently discovered that HOIL-1 is a remarkable and most unusual E3 ligase that links ubiquitin to serine and threonine residues in proteins by forming ester bonds . We have also found that the physiological substrates of HOIL-1 include the components of the Myddosome, an oligomeric complex that initiates signaling by Toll-Like Receptors (TLRs) and members of the Interleukin-1 (IL-1) family of cytokines. This exciting finding has opened up several new projects that would make interesting and challenging PhD projects. For example, how do HOIL-1-catalysed ester bonds control the production of inflammatory mediators by the innate immune system? Are other innate immune signaling pathways, such as those triggered by TNF or NOD-like receptors, also regulated by HOIL-1? Which deubiquitylases hydrolyse the ester-linked ubiquitins formed by the action of HOIL-1, and are ester-linked ubiquitins recognized by novel ubiquitin-binding proteins that decode their message? These projects will be tackled by a range of “state-of-the art” methods in my laboratory that include protein chemistry and mass spectrometry, cell and molecular biology, immunology and mouse genetics.
- Kelsall, I.R., Zhang, J., Knebel, A., Arthur, J.S.C. and Cohen, P. (2019) Proc.Natl. Acad. Sci. USA 116, 13293-13298. The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells.