PhD project

Supervisor: Matthew Freeman 

We study membrane proteins and how they control signalling and cellular responses to stress. These processes are implicated in multiple human diseases including cancer, neurodegeneration, inflammation and infection so, although we mostly do discovery science, our work has wide potential medical relevance, and we are also interested in the translational opportunities.

Our particular focus is the rhomboid-like superfamily. We were the first to discover rhomboids, and we proved that they were novel intramembrane proteases, conserved across evolution, and that they controlled growth factor signalling. Since then, the rhomboids have been implicated in many biological processes including, for example, growth factor activation, neurodegeneration, mitochondrial function, host cell invasion by parasites and bacterial physiology.

More recently we have become interested in the much wider superfamily of rhomboid-like proteins, the majority of which are not proteases. Of these non-protease rhomboid-like proteins, we especially focus on the iRhoms, which we discovered to be primary regulators of inflammation.

Our experimental approaches include genetics, cell biology, biochemistry and structural biology, mainly in mammalian cells but also with a variety of model systems. Although our main effort is aimed at understanding fundamental biology of the rhomboid-like superfamily, we are also actively pursuing the potential medical and translational significance of our basic discoveries.

Keywords:

• Biochemistry, Biotechnology, Cell Biology/Development, Genetics, Immunology, Pathology, Structural Biology

Publications:

• Lu, F., Zhao, H., Dai, Y., Wang, Y., Lee, C.H., and Freeman, M. (2024). Cryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals. Mol Cell 84, 2152–2165.e5.
• Dulloo, I., Tellier, M., Levet, C., Chikh, A., Zhang, B., Blaydon, D.C., Webb, C.M., Kelsell, D.P., and Freeman, M. (2024). Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway. Mol Cell 84, 277–292.e9.
• Tang, S., Beattie, A. T., Kafkova, L., Petris, G., Huguenin-Dezot, N., Fiedler, M., Freeman, M., and Chin, J. W. (2022). Mechanism-based traps enable protease and hydrolase substrate discovery. Nature 602, 701-707.
• Sieber, B., Lu, F., Stribbling, S. M., Grieve, A. G., Ryan, A. J., and Freeman, M. (2022). iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells. J Cell Sci 135, jcs259949.
• Dulloo, I., Atakpa-Adaji, P., Yeh, Y. C., Levet, C., Muliyil, S., Lu, F., Taylor, C. W., and Freeman, M. (2022). iRhom pseudoproteases regulate ER stress-induced cell death through IP₃ receptors and BCL-2. Nat Commun 13, 1257.
• Grieve, A. G., Yeh, Y. C., Chang, Y. F., Huang, H. Y., Zarcone, L., Breuning, J., Johnson, N., Stříšovský, K., Brown, M. H., Parekh, A. B., and Freeman, M. (2021). Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation. Mol Cell 81, 4784-4798.e7.
• Liu, G., Beaton, S. E., Grieve, A. G., Evans, R., Rogers, M., Strisovsky, K., Armstrong, F. A., Freeman, M., Exley, R. M., and Tang, C. M. (2020). Bacterial rhomboid proteases mediate quality control of orphan membrane proteins. EMBO J 39, e102922.
• Künzel, U., Grieve, A. G., Meng, Y., Sieber, B., Cowley, S. A., and Freeman, M. (2018). FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex. eLife 7, 35012.