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Signalling networks in the innate immune system
Sugar ubiquitylation; a surveillance mechanism for the recognition and elimination of misfolded macromolecules?
Ubiquitylation was discovered as a mechanism that marks proteins for destruction over 40 years ago. Since then, ubiquitylation has been found to regulate protein function in other ways, but the concept that proteins are the sole targets of ubiquitylation has never altered. Now our lab has found that carbohydrates can also be ubiquitylated.
In 2021, we discovered that mice in which the E3 ubiquitin ligase HOIL-1 is replaced by an E3-ligase inactive mutant accumulate carbohydrate deposits (termed Polyglucosan Bodies) in the brain, heart and other tissues, which are insoluble and precipitate because they lack the alpha1:6 branch points found in normal branched glycogen. HOIL-1 deficiency in humans also leads to the accumulation of Polyglucosan Bodies, causing a disease in which children develop cardiac muscle weakness, memory loss and immune defects. These observations led us to discover that the HOIL-1 E3 ligase catalyses the formation of an ester bond between the C-terminus of ubiquitin and the C6 hydroxyl group of glucose and to propose a new idea for how HOIL-1 detects abnormal glycogen molecules and initiates the process that destroys them before they precipitate and cause disease.
Our future research on this topic will now focus testing whether our hypothesis is correct. In particular, we aim to characterise the ubiquitin chains attached to unbranched glucosaccharides in cells and elucidate how ubiquitylation leads to their elimination by glycophagy, a process that may be analogous to autophagy. We will also investigate whether sugar ubiquitylation has a wider role in human health and disease than has hitherto been realised, and whether it is a surveillance mechanism for the recognition and elimination of other abnormal macromolecules. If successful, our research will open up new aspects of ubiquitin biology and enhance the understanding of diseases associated with defects in cellular quality control processes.
The role of ubiquitylation in regulating the immune system.
Our research on HOIL-1 originated with the discovery that it is an E3 ligase that attaches ubiquitin to serine and threonine residues in proteins forming ester bonds, in contrast to nearly all other E3 ubiquitin ligases that form isopeptide binds between ubiquitin and lysine residues in proteins. We recently discovered that HOIL-1 regulates immune signalling pathways both negatively and positively depending on the ligand, receptor and cell type. We are continuing to investigate how HOIL-1 and other E3 ligases regulate the immune system. We are particularly interested in understanding the physiological roles of the unique ester-linked ubiquitin dimers formed by HOIL-1 in which the C-terminus of one ubiquitin is linked to Thr12 of another ubiquitin molecule (Thr12Ub2). We will focus on identifying proteins that interact specifically with Thr12Ub2 and the identification of their biological functions.
Recent Relevant References
Role of HOIL1 in cell regulation
Kelsall, I.R., McCrory, E.H., Xu, Y., Scudamore, C.L., Nanda S.K., Mancebo-Gamella, P. Wood N.T., Knebel, A., Matthews, S.J. and Cohen, P. (2022) “HOIL-1-catalysed ubiquitylation of unbranched glucosaccharides and its activation by ubiquitin oligomers.” EMBO Journal in press bioRxiv/2021/459791 https://www.biorxiv.org/content/10.1101/2021.09.10.459791v1
Petrova, T., Zhang, J., Nanda, S., Figueras-Vadillo, C. and Cohen, P. (2021) “HOIL-1- catalysed, ester-linked ubiquitylation restricts IL-18 signaling in cytotoxic T cells but promotes TLR signalling in macrophages.” FEBS J. 288, 5909-5924
Cohen, P., Kelsall, I.R., Nanda, S.K. and Zhang, J. (2020) “HOIL-1, an atypical E3 ligase that controls MyD88 signalling by forming ester bonds between ubiquitin and components of the myddosome.” Adv. Biol. Reg. 75, 100666
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
Regulation of Immune signalling
Petrova, T., Bennett, K., Nanda, S.K., Strickson, S., Scudamore, C. and Cohen, P. (2022) “Why are the phenotypes of TRAF6 knock-in and TRAF6 knock-out mice so different?” PLoS ONE 17: e0263151 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0263151
Nanda, S.K.,,Prescott, A.R., Figueras-Vadillo, C. and Philip Cohen (2021) IKKbeta is required for the formation of the NLRP3 inflammasome EMBO Reports 22:e50743 https://doi.org/10.15252/embr.202050743
Petrova, T., Nanda, S.K., Scudamore, C., Lee, K.L., Wright, S.W., Rao, V.R. and Cohen, P. (2021) “Prevention and partial reversal of the lupus phenotype in ABIN1[D485N] mice by an IRAK4 inhibitor”. Lupus Science and Medicine 8:e000573. doi:10.1136/ lupus-2021-000573.
Darling, N.J., Arthur, J.S.C. and Cohen, P. (2021) “Salt-inducible kinases are required for the IL-33-dependent secretion of cytokines and chemokines in mast cells” J. Biol. Chem. 296,100428
Lange, S., Nelen, M., Cohen, P. and Kulathu, Y. (2021) “Dimeric Structure of the Pseudokinase IRAK3 suggests an Allosteric Mechanism for Negative Regulation” Structure 28, 238-251
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) “Distinct signals and immune cells drive liver pathology and glomerulonephritis in ABIN1[D485N] mice.” Life Science Alliance published on-line. doi: 10.26508/lsa.201900533
Recent Review Articles
Cohen, P., Cross, D. and Janne, P.A. (2021) “Kinase Drug Discovery 20 years after Imatinib: progress and future directions.” Nat. Rev. Drug Disc. 20, 551-569
Darling N.J. and Cohen, P. (2021) “Nuts and bolts of the Salt-Inducible Kinases (SIKs)” Biochem. J. 478, 1377-1397
Cohen, P. and Strickson, S. (2017) “The role of hybrid ubiquitin chains in the MyD88 and other innate immune signalling pathways.” Cell Death Diff. 24, 1153-1159 doi: 10.1038/cdd.2017.17