The Department of Biomedicine

BBB extra seminar: Sir Philip Cohen

The role of hybrid ubiquitin chains in the regulation of innate immune signalling networks

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Sir Philip Cohen
MRC Protein Phosphorylation and Ubiquitylation Unit, Sir James Black Centre, University of Dundee, Scotland, UK

The activation of Toll-like receptors (TLRs) or receptors of the interleukin-1 (IL-1) family of cytokines leads to the activation of the "master" protein kinase, TGFβ-activated protein kinase 1 (TAK1), which initiates activation of the canonical IκB kinase (IKK) complex and mitogen-activated protein (MAP) kinase cascades. These kinases in turn catalyse many phosphorylation events, which lead to production of the inflammatory mediators needed to combat infection by microbial pathogens. The activation of TAK1 involves first the formation of the Myddosome and then the dimerisation of TNF-associated factor 6 (TRAF6), which activates its E3 ubiquitin ligase activity. TRAF6 is then thought to catalyse the formation of Lys63-linked ubiquitin chains, which interact with and activate TAK1.

Met1-linked (also called linear) ubiquitin chains are also important for the activation of the canonical IKK complex. Recently, we discovered that Met1-linked ubiquitin chains are attached covalently to pre-formed Lys63-linked ubiquitin chains forming Lys63/Met1-linked hybrid ubiquitin chains. In the seminar, I will discuss the roles that hybrid ubiquitin chains play in facilitating the activation of the IKK complex and in preventing the hyper-activation of the pathway and hence the development of inflammatory and autoimmune diseases. I will also present new results, which demonstrate that TRAF6 and the linear ubiquitin assembly complex (LUBAC) are not the only E3 ligases required for hybrid ubiquitin chain formation and that TRAF6 has essential roles that are quite independent of its E3 ligase activity.

Chairperson: Jan Haavik, Department of Biomedicine