Philip Cohen's Research Group

Google Scholar | Biography


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

The Cohen lab pictured on May 19th 2022 during a walk at Kinclaven Woods, famed for its bluebells in Spring, following a lab retreat at the nearby Ballathie House Hotel about 20 miles north-west of lab. Back Row, Left to Right: Catriona Aitken, Paul Tammiste, Nicola Darling, Clara Figueras Vadillo; Front Row, Left to Right: Ian Kelsall, Philip Cohen, Tom Snelling, Tsvetana Petrova, Elisha McCrory
The Cohen lab pictured on May 19th 2022 during a walk at Kinclaven Woods, famed for its bluebells in Spring, following a lab retreat at the nearby Ballathie House Hotel about 20 miles north-west of lab. Back Row, Left to Right: Catriona Aitken, Paul Tammiste, Nicola Darling, Clara Figueras Vadillo; Front Row, Left to Right: Ian Kelsall, Philip Cohen, Tom Snelling, Tsvetana Petrova, Elisha McCrory

People

Catriona Aitken | PhD Student
Nicola Darling | Postdoctoral Researcher
Ian Kelsall | Postdoctoral Researcher
Elisha McCrory | Wellcome Trust PhD Student
Tsvetana Petrova | Postdoctoral Researcher
Tom Snelling | PhD Student

Selected Publications

  • Kelsall IR, McCrory EH, Xu Y, Scudamore CL, Nanda SK, Mancebo-Gamella P, Wood NT, Knebel A, Matthews SJ, Cohen P (2022) HOIL-1 ubiquitin ligase activity targets unbranched glucosaccharides and is required to prevent polyglucosan accumulation EMBO Journal 41 1-17
  • Petrova T, Nanda SK, Scudamore C, Wright SW, Rao VR, Cohen P (2021) Prevention and partial reversion of the lupus phenotype in ABIN1[D485N] mice by an IRAK4 inhibitor Lupus Science & Medicine 8 e000573
  • Cohen P, Cross D, Jänne PA (2021) Kinase Drug Discovery 20 years after Imatinib: progress and future directions Nature Reviews Drug Discovery 20 551-569
  • 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
  • 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
  • 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