Philip Cohen's Research Group

Pubmed | Biography


Signalling networks in the innate immune system

Bacterial and viral infections activate the signal transduction networks that regulate the innate immune system, and trigger the production of inflammatory mediators to combat the 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 the surprising discovery that hybrid ubiquitin chains (containing more than one linkage type) play a critical role in regulating the activation of the protein kinases TAK1 and IKKβ in several innate immune signalling networks. We also discovered unexpectedly that the TRAF6 and Pellino E3 ubiquitin ligases operate redundantly to produce Lys63-linked ubiquitin chains in the MyD88 signalling pathway, and that the essential roles of TRAF6 are independent of its E3 ligase function. Other projects are focussed on the role TRAF6 in regulating the adaptive immune system and on the dissection of the TLR3 signalling network, which is critical for protection against Herpes Simplex Virus Encephalitis, a devastating disease of the Central Nervous System in young children.

Cohen Lab Photo

People

Daisuke Anzai | Visiting Postdoctoral Researcher
Kyle Bennett | PhD Student
Orsolya Bilkei-Gorzo | Visiting Student
Manuel van Gijsel-Bonnello | Postdoctoral Researcher
Nicola Darling | Postdoctoral Researcher
Sumanth Iyer | Postdoctoral Researcher
Ian Kelsall | Postdoctoral Researcher
Sven M Lange | PhD Student
Sambit Nanda | Senior Research Associate
Meriam Nefla | Postdoctoral Researcher
Takashi Tanaka | Visiting Postdoctoral Researcher
Jordan Taylor | PhD Student
Jiazhen (Roy) Zhang | Postdoctoral Researcher

Selected Publications

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
Zhang, J.H., Macartney, T., Peggie, M. and Cohen, P. (2017) Interleukin-1 triggers the activation of TAK1 complexes by two mechanisms Biochem J. 474 2235-2248
Lopez-Pelaez, M., Lamont, D. J., Peggie, M., Shpiro, N., Gray, N. S., Cohen, P. (2014) Protein kinase IKKbeta-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., 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
Bakshi, S., Taylor, J., Strickson, S., McCartney, T. and Cohen, P. (2017) Identification of TBK1 complexes required for the phosphorylation of IRF3 and the production of interferon beta. Biochem J 474 1163-1174
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