Professor Sir Philip Cohen FRS FRSE FMedSci
The major goal of my research is to understand how the signal transduction networks that regulate the innate immune system are activated during infection by bacteria and viruses, and to discover how they 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. A further aim of my research is therefore to identify which components of these signalling networks are the most attractive drug targets for the treatment of these diseases. 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.
Figure 1. Early events in the MyD88 signalling network
Protein kinases are shown in red, E3 ubiquitin ligases in green, ubiquitin-binding proteins in purple and ubiquitin chains in blue
The MyD88 signaling network
We have been dissecting the MyD88-dependent signalling network (Fig 1), which is activated by the interaction of bacterial or viral products with Toll-Like receptors (TLR) and inflammatory cytokines of the Interleukin-1 (IL-1) family with their receptors. We recently made the surprising finding that hybrid ubiquitin chains, comprising both Lys63-linked and Met1-linked (or linear) ubiquitin linkages, are formed when the MyD88 and three other innate immune signalling networks are activated. These hybrid ubiquitin chains have critical roles in controlling the recruitment and activation of TAK1 and the canonical IKK complexes [1, 2], which are the “master” kinases of innate immune signalling pathways. We discovered that the formation of Met1-linked ubiquitin chains and their binding to the NEMO component of the IKK complex are required for TAK1 to initiate the activation of IKKβ, in a process completed by IKKβ itself  (Fig 1). We have also found that IKKβ activates Interferon-Regulatory Factor 5 (IRF5) as well as NF-kB . Thus, IKKβ activates the two master transcription factors that control the production of pro-inflammatory cytokines, IRF5 and NF-κB (Fig 1).
We noticed that the interaction of Lys63/Met1-ubiquitin hybrids with ABIN1 restrains the activation of the MyD88 signaling network and prevents the development of lupus nephritis, a severe autoimmune disease . The mice we generated in which ABIN1 is replaced by a mutant unable to bind to the Lys63/Met1-ubiquitin hybrids develop lupus nephritis spontaneously. However, excitingly, we have found that the disease can be completely prevented by crossing to mice in which the IRAK1 or IRAK4 protein kinases have been replaced by catalytically inactive mutants. These studies have validated IRAK1 and IRAK4 as potential targets for the development of drugs to treat lupus . This is important because, in recent years, human polymorphisms in ABIN1 have been shown to predispose to lupus and other autoimmune diseases in eight different human populations. We are also beginning to make progress in understanding the molecular mechanism by which ABIN1 protects against autoimmune disease.
The MyD88 signaling network not only produces pro-inflammatory cytokines to fight infection, but also anti-inflammatory molecules, such as IL-10, which have important roles in terminating inflammation once it has done its job. We discovered that members of the SIK family of protein kinases (SIK1, SIK2 and SIk3) inactivate CRTC3, a co-activator of the transcription factor CREB that is a key driver of IL-10 gene transcription. We identified the first potent inhibitors of the SIKs and found that they transform macrophages from an inflammatory M1 phenotype to the anti-inflammatory M2b phenotype thought to be critical for the resolution of inflammation  (Fig 1). We have generated knock-in mice in which the three SIKs have been replaced by kinase-inactive mutants and crossed them with one another to produce double knock-in mice. We have used macrophages from these mice to provide genetic validation of our earlier results (Darling et al, submitted) and are now investigating whether macrophage driven inflammatory and autoimmune diseases are prevented in SIK knock-in mice to evaluate the therapeutic potential of drugs that inhibit the SIKs.
Over the past year we have made several unexpected findings, which challenge widely held views about how the early signalling events of the MyD88 pathway are initiated. These findings have opened up several exciting new projects in my lab.
The TRIF signalling pathway.
We have become interested in unravelling the early events in the TLR3 signalling network, which is activated by viral double-stranded RNA and signals not through MyD88, but via the distinct adaptor protein TRIF. The activation of this pathway is critical for protection against Herpes Simplex Virus Encephalitis, a devastating disease of the Central Nervous System in young children who have inactivating mutations in proteins that participate in this signalling network. We are particularly interested in discovering how this pathway triggers the activation of the protein kinase TBK1, which is required to activate the transcription factor IRF3 and hence the production of interferon β. We have discovered that TBK1 is activated by a novel mechanism, which we are now trying to elucidate
Relevant recent lab publications cited – members of the Cohen lab are highlighted in boldface type.
- Emmerich, C. H., Ordureau, A., Strickson, S.., Arthur, J. S., Pedrioli, P. G., Komander, D. and 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
- Emmerich, C. H., Bakshi, S., Kelsall, I. R., Ortiz-Guerrero, J., Shpiro, N. and Cohen, P. (2016) Lys63/Met1-hybrid ubiquitin chains are commonly formed during the activation of innate immune signalling. Biochem. Biophys. Res. Commun. 474, 452-461
- Zhang, J., Clark, K., Lawrence, T., Peggie, M. W. and Cohen, P. (2014) An unexpected twist to the activation of IKK β: TAK1 primes IKK β for activation by autophosphorylation. Biochem. J. 461, 531-537
- Lopez-Pelaez, M., Lamont, D. J., Peggie, M., Shpiro, N., Gray, N. S. and Cohen, P. (2014) Protein kinase IKK β-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells. Proc. Natl. Acad. Sci. U. S. A. 111, 17432-17437
- Nanda, S. K., Venigalla, R. K., Ordureau, A., Patterson-Kane, J. C., Powell, D. W., Toth, R., Arthur, J. S. and Cohen, P. (2011) Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. J. Exp. Med. 208, 1215-1228
- 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. and 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
- Goh, E. T. H., Arthur, J. S. C., Cheung, P. C. F., Akira, S., Toth, R., and Cohen, P. (2012) Identification of the protein kinases that activate the E3 ubiquitin ligase Pellino 1 in the innate immune system Biochem. J. 441, 339-346
- Smith, H., Liu, X-Y., Dai, L., Goh, E.T.H., Chan, A-T., Xi, J., She, C-C., Qureshi, I.A., Ruedl, C., Gourlay, R., Morton, S., Hough, J., McIver, E.G., Cohen, P. and Cheung, P.C.F. (2011) The role of TBK1 and IKKε in the expression and activation of Pellino 1. Biochem. J. 434, 537-548
- Enesa, K., Ordureau, A., Smith, H., Barford, D., Cheung, P.F.C., Arthur, J.S., and Cohen, P. (2012) Pellino1 is required for interferon production by viral double-stranded RNA. J. Biol. Chem. 287, 34825-34835
- Ordureau, A., Enesa, K., Nanda, S., Le Francois, B., Peggie, M., Prescott, A., Albert, P. R. and Cohen, P. (2013). DEAF1 Is a Pellino1-interacting Protein Required for Interferon Production by Sendai Virus and Double-stranded RNA. J Biol Chem 288, 24569-24580
- Clark, K., Peggie, M., Plater, L., Sorcek, R.J., Young, E.R.R., Madwed, J.B., Hough, J., McIver, E.G. and Cohen, P. (2011) Novel cross-talk within the IKK family controls innate immunity. Biochem. J. 434, 93-104
- Clark, K., Takeuchi, O., Akira, S. and Cohen, P. (2011) TANK facilitates crosstalk within the IKK family during TLR signaling. Proc. Natl. Acad. Sci. USA. 108, 17093-17098
- Nanda, S.K., Venigalla, R.K.C., Ordureau, A., Patterson-Kane, J.C., Powell, D.W., Toth, R.J., Arthur, J.S.C. and Cohen, P. (2011) Polyubiquitin binding to ABIN1 is required to prevent autoimmunity J. Exp. Med. 208, 1215-1228
- Gleason, C.E., Ordureau, A., Gourlay, R., Arthur, J.S.C. and Cohen , P. (2011) Polyubiquitin binding to optineurin is required for optimal activation of TANK-binding kinase 1 and the production of interferon β J. Biol. Chem. 286, 35663-35674
- Clark, K., Nanda, S. and Cohen, P. (2013). Molecular control of the NEMO family of ubiquitin-binding proteins. Nat Rev Mol Cell Biol
- 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 of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages Proc Natl Acad Sci USA 109, 16986-16991
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