Professor Sir Philip Cohen FRS FRSE FAA FFMedSci
Bacterial and viral infections activate the signal transduction networks that regulate the innate immune system, and trigger the production of inflammatory mediators to combat these pathogens. Understanding these signalling networks is important, not just because it may lead to the development of improved drugs to fight infection, but also because failure to control the production of inflammatory mediators causes major global diseases, such as arthritis, asthma, colitis, fibrosis, lupus, psoriasis and sepsis.
My group studies the activation and output of these signalling networks, and we also aim to identify which components are attractive drug targets for the treatment of disease. Another focus is to understand the interplay between protein phosphorylation and protein ubiquitylation in regulating the innate immune system, which we tackle by using a range of state-of-the-art techniques that include molecular, cellular and chemical biology, protein chemistry, mass spectrometry and mouse genetics.
Recently, we have made several unexpected discoveries. First, that hybrid ubiquitin chains containing several linkage types play critical roles in regulating innate immune signalling networks; second that the essential roles of TRAF6 in initiating innate immune signalling are independent of its E3 ligase activity; third that the HOIL-1 component of the Linear Ubiquitin Assembly Complex (LUBAC) is a remarkable E3 ligase that attaches ubiquitin to serine and threonine residues in proteins by forming ester bonds. Current projects are focused on understanding how the HOIL-1 E3 ligase controls innate immune signalling, why the SIK family of protein kinases are required for pro-inflammatory cytokine production, and why the TRAF6 E3 ligase restricts T cell activation. We are also studying how the ubiquitin-binding protein ABIN1 restricts activation of the MyD88-IRAK4-IRAK1 signaling axis to prevent lupus, and dissecting the TLR3 signaling network, which is critical for protection against Herpes Simplex Virus Encephalitis, a devasting disease of the central nervous system in young children.
Nanda, S.K., Tsvetana, T., Francesco Marchesi, Marek Gierlinski, Momchil Razsolkov, Katherine L. Lee, Stephen W. Wright, Vikram R. Rao, Philip Cohen and J. Simon C. Arthur (2019) Life Science Alliance published on-line. doi: 10.26508/lsa.201900533
Kelsall, I. R., Zhang, J., Knebel, A., Arthur, J. S. C. and Cohen, P (2019) The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells Proceedings of the National Academy of Sciences 116 13293-13298
Nanda, S. K., Nagamori, T., Windheim, M., Amu, S., Aviello, G., Patterson-Kane, J., Arthur, J. S. C., Ley, S. C., Fallon, P. and Cohen, P (2018) ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism Journal of immunology 201 3373-3382
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 signaling in mammalian cells Proc. Natl. Acad. Sci. USA 10 1073/pnas/1702367114
Zhang, J.H., Macartney, T., Peggie, M. and Cohen, P. (2017) Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3 Biochem J. 474 2235-2248
Nanda, S. K., Lopez-Pelaez, M., Arthur, J. S., Marchesi, F. and Cohen, P. (2016) Suppression of IRAK1 or IRAK4 Catalytic Activity, but Not Type 1 IFN Signaling, Prevents Lupus Nephritis in Mice Expressing a Ubiquitin Binding-Defective Mutant of ABIN1. J Immunol 197 4266-4273
Emmerich, C. H., Ordureau, A., Strickson, S., Arthur, J. S., Pedrioli, P. G., Komander, D., Cohen, P. (2013) Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains Proc Natl Acad Sci U S A 110 15247-15252
Pauls, E., Nanda, S. K., Smith, H., Toth, R., Arthur, J. S. and Cohen, P. (2013) Two phases of inflammatory mediator production defined by the study of IRAK2 and IRAK1 knock-in mice. J Immunol. 191, 2717-2730 doi. 10.4049/jimmunol.1203268. Pubmed. 23918981, PMC 3849919
Clark, K., MacKenzie, K.F., Petkevicius, K., Kristariyonto, Y., Zhang, J., Choi, H.G., Peggie, M., Plater, L., Pedrioli, P.G.A., McIver, E., Gray, N.S., Arthur, J.S.C. and Cohen, P. (2012) Phosphorylation or CRTC3 by the salt-inducible kinases controls the interconversin of classically activated and regulatory macrophages Proc Natl Acad Sci USA 109, 16986-1699
In addition to establishing the DSTT research collaboration with the pharmaceutical industry I helped to establish a new company based in Dundee to commercialise the MRC PPU’s phosphorylation reagents and also the kinase profiling service that I established. The company (Upstate) was acquired by Serologicals Corp in 2004 for $205 million which became a subsidiary of Millipore Corp which was acquired by Merck KGaA in 2010. In 2009 I helped to establish Ubquigent, a Dundee based SME that commercialises reagents in the Ubiquitin field