Research Article: Independent Pathways Can Transduce the Life-Cycle Differentiation Signal in Trypanosoma brucei

Date Published: October 17, 2013

Publisher: Public Library of Science

Author(s): Balazs Szöőr, Naomi A. Dyer, Irene Ruberto, Alvaro Acosta-Serrano, Keith R. Matthews, Kent L. Hill.


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.

Partial Text

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]. Additionally, the presence of multiple cues can lower the threshold at which cells respond to differentiation signals or refine their response, with inputs from distinct signalling pathways co-operating to generate a specific developmental outcome (e.g. [2], [3]). In this way, quite sophisticated perception mechanisms can contribute to ensure an appropriate and timely developmental response when cells encounter conditions where differentiation is the optimal survival response to a changing environment.

When ingested in a tsetse fly bloodmeal trypanosomes rapidly initiate differentiation in order to adapt to their new environment. Our earlier studies have demonstrated that the CCA differentiation signal is transduced via PAD proteins through a phosphatase-signalling cascade, whereby TbPTP1 is inactivated and TbPIP39 becomes phosphorylated and activated [20]–[22]. Here we have used these components to investigate the molecular basis of differentiation initiated by CA and to demonstrate that independent signalling pathways can operate to stimulate development.




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