Abstract
African trypanosomes cause disease in humans and livestock, generating significant health and welfare problems throughout sub-Saharan Africa. When ingested in a tsetse fly bloodmeal, trypanosomes must detect their new environment and initiate the developmental responses that ensure transmission. The best-established environmental signal is citrate/cis aconitate (CCA), this being transmitted through a protein phosphorylation cascade involving two phosphatases: one that inhibits differentiation (TbPTP1) and one that activates differentiation (TbPIP39). Other cues have been also proposed (mild acid, trypsin exposure, glucose depletion) but their physiological relevance and relationship to TbPTP1/TbPIP39 signalling is unknown. Here we demonstrate that mild acid and CCA operate through TbPIP39 phosphorylation, whereas trypsin attack of the parasite surface uses an alternative pathway that is dispensable in tsetse flies. Surprisingly, glucose depletion is not an important signal. Mechanistic analysis through biophysical methods suggests that citrate promotes differentiation by causing TbPTP1 and TbPIP39 to interact.
Highlights
Eukaryotic developmental events are a response to single or multiple external cues
African trypanosomes are important pathogens transmitted by tsetse flies in sub-Saharan Africa
We monitored TbPIP39 phosphorylation to show that two signalling pathways operate: one signalled by citrate or mild acid, the other stimulated by external protease activity
Summary
Eukaryotic developmental events are a response to single or multiple external cues. Commonly, the existence of multiple cues ensures that cells do not embark prematurely on a developmental process that could damage their viability or fitness [1]. Cell type differentiation is most studied in the programmed specialisation of metazoan cells as they form tissues or adapt for particular functions in the body, unicellular organisms can undergo development in response to external signals Exemplary of this are the differentiation responses of vector-borne parasites. Among the best studied of these are the kinetoplastid parasites, representing the earliest branching extant eukaryotes [6] that are responsible for a range of tropical diseases such as visceral and cutaneous Leishmaniases (caused by different Leishmania spp.), American trypanosomiasis (‘Chagas’ disease’, caused by Trypanosoma cruzi) and Human, and Animal, African trypanosomiasis (HAT, AAT, caused by Trypanosoma brucei [7]) For both Leishmania and T. cruzi several signals have been discovered that can trigger life-cycle differentiation including low temperature, pH balance [8] and, most recently in Leishmania, iron availability [9]. The molecular details of the development from slender to stumpy forms are not well
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