An atypical DYRK kinase connects quorum-sensing with posttranscriptional gene regulation in Trypanosoma brucei
- School of Biological Sciences, University of Edinburgh, United Kingdom
- University of Cambridge, United Kingdom
Abstract
The sleeping sickness parasite, Trypanosoma brucei, uses quorum sensing (QS) to balance proliferation and transmission potential in the mammal bloodstream. A signal transduction cascade regulates this process, a component of which is a divergent member of the DYRK family of protein kinases, TbDYRK. Phylogenetic and mutational analysis in combination with activity and phenotypic assays revealed that TbDYRK exhibits a pre-activated confirmation and an atypical HxY activation loop motif, unlike DYRK kinases in other eukaryotes. Phosphoproteomic comparison of TbDYRK null mutants with wild type parasites identified molecules that operate on both the inhibitory 'slender retainer' and activatory 'stumpy inducer' arms of the QS control pathway. One of these molecules, the RNA-regulator TbZC3H20, regulates parasite QS, this being dependent on the integrity of its TbDYRK phosphorylation site. This analysis reveals fundamental differences to conventional DYRK family regulation and links trypanosome environmental sensing, signal transduction and developmental gene expression in a coherent pathway.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
Wellcome (103740/Z14/Z)
- Keith Matthews
Royal Society (WM140045)
- Keith Matthews
European Commission (65470)
- Mathieu Cayla
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experiments in this work were carried out in accordance with the local ethical approval requirements of the University of Edinburgh and the UK Home Office Animal (Scientific Procedures) Act (1986) under licence number 60/4373.
Copyright
© 2020, Cayla et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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An atypical DYRK kinase connects quorum-sensing with posttranscriptional gene regulation in Trypanosoma brucei
eLife 9:e51620.
https://doi.org/10.7554/eLife.51620
