TRYP-QS · YAK kinase regulated trypanosome quorum sensing
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-05-05 → 2017-05-04
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
YAK kinase regulated trypanosome quorum sensing
Trypanosomes are responsible for human African trypanosomiasis and the cattle disease nagana. Both have devastating impact in Sub Saharan Africa and are transmitted by tsetse flies. In preparation for transmission, the parasites differentiate in each wave of parasitaemia from proliferative 'slender' forms to non-proliferative, transmissible, 'stumpy' forms. This represents a density-dependent or 'quorum sensing' (QS) response mediated by an unidentified soluble parasite released factor, stumpy induction factor (SIF). However, the molecular pathway that transduces the SIF response within the parasites has been characterised by a genetic screen. One of the molecules identified was a predicted protein kinase that resembled the YAK kinase family of proteins that operate in other eukaryotes to control cellular dormancy. This represented a potentially fundamental and evolutionarily conserved component of the parasites' developmental response pathway, that could also provide information of the development of other eukaryotic pathogens that exhibit growth control and environmental responses during their life cycle. YAK kinases sometimes exhibit relocation to the nucleus upon activation, although in trypanosomes post transcriptional (and therefore potentially cytoplasmic focused) regulation supersedes nuclear transcriptional control as the main regulatory mechanism. Hence the location and interactions of the YAK kinase is of interest, an intriguing observation being the potential of the protein to interact with a class of proteins (called '14-3-3') through a C-terminal binding domain. In the work, the expertise of the fellow and his experience in the analysis of protein kinase function at the Institut Pasteur was to be applied to the understanding of the location, function and substrates/interactants of the YAK kinase identified in the trypanosome QS pathway.
Data: CORDIS, © European Union
Project objective
African trypanosomes are parasites that cause disease in both humans and livestock throughout sub Saharan Africa, leading to death and hardship in afflicted regions. The disease is spread by blood-feeding tsetse flies and trypanosomes use sophisticated mechanisms to sense their environment in order to optimise their chances of transmission. In particular, whilst in the host bloodstream trypanosomes communicate with one another to monitor their own population density, this determining when they produce specialised transmission stages (so called ‘Stumpy’ forms). We have recently identified, using a genome-wide RNAi screen, components of the signal transduction pathway that drive this quorum sensing (QS) response. One component seems pivotal in the pathway- a molecule related to the YAK kinase of proteins. In yeasts and slime molds YAK kinase contributes to cell growth arrest in response to extracellular signals including nutrient limitation, whilst in mammals, related molecules of the DYRK family can also act in cellular quiescence. In this proposal we will investigate the function of trypanosome YAK kinase in the parasite's QS response. Specifically, we will investigate the kinase function in vitro and in vivo and dissect its action by following its location and targets. These are likely to differ from the situation in yeasts where YAK relocates to the nucleus and changes mRNA expression; in trypanosomes gene regulation is almost exclusively post transcriptional and likely operates within the cytoplasm. The function, location and interactions of YAK kinase in the QS signalling pathway is expected to provide comprehensive insight into how trypanosome parasites control their development in preparation for transmission, with additional important relevance for related parasites including other kinetoplastids and malaria. A two way benefit, encompassing training and expertise exchange between the researcher and host laboratory, will also be established.
Original text from CORDIS.
Participants
- THE UNIVERSITY OF EDINBURGH · EdinburghCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union