Research
The rhomboid-like clan: the cell biology of pseudoproteases
Members of the rhomboid-like superfamily of proteins are related to rhomboid intramembrane serine proteases. Despite showing clear rhomboid homology, most lack the hallmark proteolytic residues. The pseudoproteases in this rhomboid-like superfamily include the iRhoms, but also other distantly related proteins.
Work from our lab and others has highlighted the wide range of cellular control processes in which rhomboid-like proteins participate. There is also growing evidence for their role in diverse human diseases. We aim to understand the cellular, physiological and disease functions of the rhomboid-like superfamily.
Our recent work has focused on the iRhoms. In mammals, including humans, we have discovered a different role for iRhoms in regulating inflammation and growth factor signalling. By regulating the cellular trafficking, and therefore the activity, of the enzyme TACE, iRhoms are essential regulators of the inflammatory cytokine TNF. Since TACE also controls the release of other factors, including EGF receptor ligands, this gives iRhoms the potential of being regulatory hubs for multiple signalling pathways.
We are also investigating the role of iRhoms in ER associated degradation (ERAD). In Drosophila, we have shown that iRhom promotes ERAD of EGF receptor ligands, thereby regulating EGFR activity in the brain.
We also study more distant member of the rhomboid-like clan, whose function remains completely unknown. We are interested in discovering whether there are mechanistic common themes that reflect the shared evolutionary history of members of the clan, as well as understanding their disease relevance.
Rhomboids - unusual proteases with diverse biological functions
Our work on the rhomboid-like superfamily started when we discovered that rhomboids are a novel family of serine proteases that cleave substrates within transmembrane domains (TMDs). All rhomboids have multiple TMDs (typically six or seven). Their mechanism depends on an unusual catalytic dyad between conserved serine and histidine residues positioned in hydrophobic TMD-segments. The crystal structures of rhomboids provide significant clues about their detailed mechanism.
The rhomboid family are members of an exclusive club of proteases that have the unusual property of cleaving proteins within their TMDs, actually cutting in the membrane bilayer. Most of these control important signalling processes. Beyond the rhomboids, the presenilins and signal peptide peptidase are intramembrane aspartyl proteases; they cleave substrates including the Notch receptor and the amyloid precursor protein, which is implicated in Alzheimer's disease. The site-2 protease family are intramembrane metalloproteases; among other things, they regulate cholesterol biosynthesis and the unfolded protein response. The different intramembrane protease families are evolutionarily and mechanistically unrelated, but there are clear common functional themes that link them.
We remain interested in a number of related questions about how rhomboids function and what they do. We discovered that rhomboids are activators of EGF receptor signalling in Drosophila, but they exist throughout evolution, from bacteria and archaea to humans. We now know that they control important areas of mitochondrial biology, participate in apicomplexan parasite invasion of host cells, and at least on one case regulate protein secretion in bacteria. One obvious gap that we would like to fill is to discover their primary physiological role in mammals. Another major open question is how rhomboids are regulated: they are potentially dangerous enzymes in cells, and we don’t understand how they are prevented from cutting the wrong proteins at the wrong time. Finally, we’d like to know their relevance to human disease.
Genes of unknown function
We are developing genetic techniques to investigate systematically the still large number of genes that have no known function. As well as systematic approaches, we are using bioinformatic tools to select particularly interesting examples for intensive study.