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 conformation 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.
Highlights
Eukaryotic cells respond to their environment via signal transduction cascades whose general structure and features have been intensively studied in model eukaryotes
To initially analyse the gene Tb927.10.15020, we performed a phylogenetic analysis using the kinase core of all members of the CMGC kinase family from human, C. elegans, D. melanogaster, S. cerevisiae and all identified members of the dualspecificity yak-related kinases (DYRK) family from T. brucei (Jones et al, 2014)
The analysis revealed that Tb927.10.15020 is a divergent DYRK belonging to a paraphyletic group of DYRK2 (Figure 1a)
Summary
Eukaryotic cells respond to their environment via signal transduction cascades whose general structure and features have been intensively studied in model eukaryotes These enable the adaptation to a changing environment or response to external signals that regulate cellular differentiation and specialisation. A tractable model to explore the diversity of eukaryotic signalling networks are kinetoplastid parasites, which separated from the eukaryotic lineage at least 500 million years ago (Keeling and Burki, 2019). These organisms encode around 190 protein kinases (Jones et al, 2014) and are exquisitely sensitive to their environment. One major environmentally signalled event for T. brucei involves their differentiation in the mammal host from a replicative ‘slender form’
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