Domingo Sananes et al. investigate how the parasite Trypanosoma brucei transitions between different developmental stages.

Many protozoan parasites undergo complex life cycles that require their adaptation to drastically different environments. T. brucei, for example, must switch from a growth-arrested “stumpy” form in mammalian blood to a proliferative “procyclic” form in the tsetse fly gut. In vitro, this differentiation step can be induced by cis-aconitate (CA). Domingo Sananes et al. found that the parasite only responded above a threshold of 1 mM CA but that, after exposure to this signal for 2–3 hours, the cells were committed to differentiation, even if CA was subsequently depleted from the surrounding medium.

The stumpy-to-procyclic transition is therefore an irreversible bistable switch, a mechanism commonly used to govern biological events such as differentiation or mitotic entry. In vivo, the switch would aid parasite survival by making their differentiation quick and decisive.

Domingo Sananes et al. discovered that protein synthesis was required for T. brucei to “remember” the CA signal and retain their commitment to differentiation. Accordingly, the parasite’s proteome showed numerous changes after three hours of CA exposure. Differentiation was also accompanied by many changes in protein phosphorylation. The researchers focused on a protein kinase, NRK, that is highly expressed in stumpy cells and found that knocking down this kinase inhibited the parasite’s transition to the procyclic form.

Author Keith Matthews now wants to investigate how NRK promotes Trypanosome differentiation, and to determine how it is linked to upstream signaling events that initiate the response to CA.


Domingo Sananes
, et al
J. Cell Biol.

Author notes

Text by Ben Short