Membrane proteins make up about 30% of the human proteome and represent over half of all drug targets. We investigate the interface between membrane proteins, the cell biology of signalling, and mechanisms of human disease. Our particular focus is the rhomboid-like superfamily, which we discovered, and which are increasingly recognised as being multi-functional regulators of a wide range of membrane proteins.
Rhomboid protease and pseudoprotease.
Sliver from wild type (left) and RHBDL4 KO (right) mice, showing pathological accumulation of fat, labelled in red, in the absence of the rhomboid RHBDL4.
Membrane proteins control a wide range of fundamental biological processes and are the targets of more than half of current drugs. Our research focuses on the interface between membrane proteins, the cell biology of signalling, and mechanisms of human disease.
Using genetics to investigate the mechanisms of signalling between cells, we discovered that rhomboids were novel proteases, conserved across evolution, which regulate the production of extracellular signals. Rhomboids are intramembrane proteases, unrelated to more classical enzymes, and were found to catalyse the cleavage of transmembrane domains. The rhomboids are now known to be involved in a very wide range of biologically and medically important processes.
We subsequently discovered that the rhomboid proteases were the tip of an iceberg: the majority of the superfamily of rhomboid-like proteins have lost their protease activity during evolution. We have studied a few examples of these ‘pseudoproteases’ and have uncovered roles in controlling the fate of a wide range of membrane proteins. Our working hypothesis is that the fundamental role of the rhomboid-like domain is specific recognition of transmembrane domains. Among other functions, we have discovered roles for pseudoprotease rhomboid-like proteins in controlling inflammation, cancer and signalling.
The overall theme of our research is to understand, and learn how to manipulate, the regulatory processes that control signalling, and that shape the membrane proteome more widely. Using cell biology and genetics, as well as molecular and structural techniques, we seek to understand both the molecular mechanisms, but also the significance of these processes in fundamental biology and human disease. For example, we have revealed central roles for rhomboid-like proteins in inflammatory diseases and cancer.
2022
iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells.
Sieber, B., Lu, F., Stribbling, S.M., Grieve, A.G., Ryan, A.J., and Freeman, M.
J Cell Sci. – 135(17): jcs259949.
2022
Mechanism-based traps enable protease and hydrolase substrate discovery.
Tang, S., Beattie, A.T., Kafkova, L., Petris, G., Huguenin-Dezot, N., Fiedler, M., Freeman, M. and Chin, J.W.
Nature – 602(7898): 701-707.
2021
Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation.
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.
Molecular Cell – 81(23): 4784-4798.e7.
2020
ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet-mediated degeneration.
Muliyil, S., Levet, C., Düsterhöft, S., Dulloo, I., Cowley, S.A., and Freeman, M.
EMBO J. – 39(17): e104415.
2018
FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex.
Künzel, U., Grieve, A.G., Meng, Y., Sieber, B., Cowley, S.A. and Freeman, M.
eLife – 7: e35012.
2017
Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling.
Grieve, A.G., Xu, H., Künzel, U., Bambrough, P., Sieber, B. and Freeman, M.
eLife – 6: e23968.
2012
Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE.
Adrain, C., Zettl, M., Christova, Y., Taylor, N. and Freeman, M.
Science – 335(6065): 225-8.
Dunn School postdocs start new PI positions
October 2025
Congratulations to the Dunn School postdocs starting their own independent groups!
Dunn School Researchers Support Community Collaborations in Science Together Programme
July 2024
iRhom2’s Pseudoprotease Cleavage Unveils a Novel ER-to-Nucleus Signalling Pathway
January 2024
“The Unknome”: The database of neglected proteins created by Dunn School researchers
August 2023
A new collaborative study led by Matthew Freeman shows that a fifth of the human genome remains poorly characterised, and further highlights that many of these mystery genes could have vital functions in diverse biological processes.