Species from several fungal genera, including Candida, Aspergillus, Pneumocystis and Cryptococuss have the potential to give rise to serious clinical infections and are estimated to cause 1.5 million deaths per year. Despite their importance as human pathogens, our understanding of how they affect immune cells, and how this might be affected by the presence of other pathogens is incomplete.
Chinese Scholarship Council Programme
Most of our food calories come from cereal grain. The development of cereal plants strongly influences the amount of harvested grain or its yield. Cereal stems elongate when they flower (1). Tall cereals easily fall over, a devastating event for farmers, so controlling cereal height is important for cereal breeders. We recently discovered that jasmonate, a classic plant stress/defense hormone, strongly inhibits both flowering and stem elongation in barley (2), suggesting that the jasmonate pathway may be a good breeding target.
Phosphorylation is a major posttranslational modification whose disruption is linked to multiple human diseases. Our lab has recently found a link between the Parkinson’s associated protein kinase PINK1 and a subset of Rab GTPases. This project will employ state-of-the-art methods to uncover the regulation of Rabs by PINK1 in cells .
The project will lead to training in a wide array of technologies including mass spectrometry and biochemistry. The lab is also linked to the EMBO network and the student will also benefit from training opportunities in Europe during their studies.
Recent work from our group has shown the value in analysing paralogous gene families to boost the functional signal in data from DNA sequencing human exomes and genomes at the population level (MacGowan et al, 2017). The signal is especially strong in families of protein repeats such as TPRs, Ankyrins, HEAT and Armadillo and our recent collaborative research has shown how population genetics data can be used to select variants least likely to perturb function (Llabrés et al, 2019). The project will extend these principles to a wider range of protein families important in disease.
The Linear Ubiquitin Assembly Complex (LUBAC) contains two E3 ubiquitin ligases, called HOIP and HOIL-1. HOIP catalyses the formation of Met1-linked ubiquitin (also called linear ubiquitin) chains, which are required to activate the IkB kinase (IKK) complex that switches on the master transcription factors of the innate immune system, NF-kB and IRF5 (interferon regulatory factor 5). In contrast, we have recently discovered that HOIL-1 is a remarkable and most unusual E3 ligase that links ubiquitin to serine and threonine residues in proteins by forming ester bonds .
Phytophthora species are amongst the most devastating causes of disease on dicot plants. Chief amongst them is P. infestans, cause of late blight, the number one disease globally on potato and tomato. P. infestans is able to secrete proteins called effectors which are delivered inside living plant cells to manipulate various processes, including host immunity. Our group study the secretion, post-translational processing and delivery of so-called RXLR effectors. RXLR effectors may target host proteins to alter, promote or prevent their functions.
Ubiquitination is a posttranslational modification that regulates all aspects of physiology and aberrant ubiquitination has been implicated with numerous diseases. Ubiquitination is typically considered a posttranslational modification of lysine residues but it is emerging that non-lysine ubiquitination is intrinsic to mammalian biology. This project will use a multidisciplinary approach to understand the cellular function of non-lysine ubiquitination.
The Findlay lab employs cutting-edge technologies to unravel Embryonic Stem (ES) cell signalling networks (Williams et al, Cell Rep 2016, Fernandez-Alonso et al, EMBO Rep 2017; Bustos et al, Cell Rep 2018), culminating in our recent discovery of the ERK5 pathway as an exciting new regulator of ES cell pluripotency. In order to uncover functions of ERK5 in ES cells, this project will deploy global quantitative phosphoproteomic, proteomic and transcriptomic (RNA-SEQ) profiling.
The Ganley lab is interested in unravelling the molecular mechanism of autophagy (which literally translates from the Greek meaning to eat oneself). Autophagy is a lysosomal degradation pathway that functions to clear the cell of potentially damaging agents, such as protein aggregates or faulty mitochondria, as well as acting as a recycling station to supply essential building blocks during periods of starvation.