The E3 ubiquitin ligase TRAF6 is known to have an essential role in the signalling networks triggered by infection with microbial pathogens, by pro-inflammatory cytokines of the Interleukin-1 (IL-1) family and by many TNF superfamily members. For these reasons, mice that do not express TRAF6 have many adverse phenotypes, such as the absence of hair follicles, sweat glands and teeth, and deformed bones. They are unable to produce dendritic cells, their myeloid cells do not secrete any cytokines when stimulated with activators of Toll-Like Receptors (TLRs), they are small and they die with two weeks of birth. We recently made the unexpected discovery that the E3 ubiquitin ligase activity of TRAF6 was dispensable for signalling by TLRs or IL-1, which led us to make a knock-in mice in which TRAF6 was replaced by the E3 ligase-inactive TRAF6[L74H] mutant. Remarkably, this knock-in mouse did not have any of the phenotypes of the TRAF6 knock-out mouse, but an entirely different one. The TRAF6[L74H] mice had an enlarged spleen and lymph nodes, the T cells in these tissues were in a highly activated state and the mouse developed an autoimmune disease and severe inflammation of many organs within three weeks. These observations indicate that, surprisingly, the key role for the TRAF6 E3 ligase in vivo is to restrict the activation of T cells to prevent autoimmune disease. These findings indicate that the “textbook” accounts of how TRAF6 regulates biological processes are incorrect and that the essential roles of TRAF6 in many signalling networks require re-investigation. I am therefore offering a project in which the student will investigate why TRAF6, but not its E3 ligase activity, is essential for signalling by the TNF superfamily member RANKL, which controls the formation of osteoclasts, dendritic cells, sweat glands and other processes and underlies many of the adverse phenotypes of the TRAF6 knock-in mouse.
Strickson, S., Emmerich, C.H., Goh, E.T.H., Zhang, J., Kelsall, I.R., McCartney, T., Hastie, C.J. ,Knebel,A., Peggie, M., Marchesi, F., Arthur, J.S.C. and Cohen, P. (2017) The role of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signalling in mammalian cells Proc. Natl. Acad. Sci. USA E3481–E3489, doi: 10.1073/pnas.1702367114