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

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Szöőr, Balazs ; Dyer, Naomi A. ; Ruberto, Irene ; Acosta-Serrano, Alvaro ; Matthews, Keith R. (2013)

Author Summary African trypanosomes are important pathogens transmitted by tsetse flies in sub-Saharan Africa. Upon transmission, trypanosomes detect citrate and cis-aconitate in the bloodmeal, this inactivating a negative regulator of differentiation, the tyrosine phosphatase TbPTP1. One TbPTP1 substrate is another phosphatase, TbPIP39, which is more active when phosphorylated (after TbPTP1 inhibition) and promotes differentiation. These differentiation regulators have provided tools to monitor whether one or more environmental signals are used to initiate trypanosome development and their relevance in vivo. This is important because different studies over the last 30 years have disputed the physiological importance of different signals. Here we have, firstly, compared the efficacy of the different reported differentiation signals, establishing their relative importance. We then monitored TbPIP39 phosphorylation to show that two signalling pathways operate: one signalled by citrate or mild acid, the other stimulated by external protease activity. Thereafter, we showed that, of these different signals, protease activity is dispensable for differentiation in tsetse flies. Finally, we used biophysical methods to investigate how citrate causes TbPIP39 and TbPTP1 to interact, enabling their regulatory cross-talk. These studies have established the importance of different developmental signals in trypanosomes, providing molecular insight into how the development signal is transduced within the pathogen.