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Sci. Signal., 22 June 2010
Vol. 3, Issue 127, p. ec186
[DOI: 10.1126/scisignal.3127ec186]

EDITORS' CHOICE

Parasitology Bistable Trypanosome Switch

Annalisa M. VanHook

Science Signaling, AAAS, Washington, DC 20005, USA

The protozoan parasite Trypanosoma brucei, the causative agent of sleeping sickness, adopts metabolically and morphologically distinct forms as it proceeds through its life cycle. Both "slender" (nontransmissible) and "stumpy" (transmissible) forms of the trypanosome circulate in the bloodstream of the mammalian host. When ingested by the tsetse fly, the drop in temperature causes an increase in the amount of citrate and cis-aconitate (CCA) transported into the cell, which, in turn, triggers differentiation into the procyclic form that colonizes the fly gut. Activity of the tyrosine phosphatase TbPTP1 is required to maintain the stumpy form, and inactivated TbPTP1 is associated with differentiation into the procyclic form. Using a substrate-trapping version of TbPTP1 that could bind to but not release substrate, in conjunction with various in vitro and in vivo assays performed with trypanosomes that were maintained in mice and differentiated by culturing at 20°C with CCA, Szöor et al. identified the phosphatase TbPIP39 as an in vivo substrate for TbPTP1. Phosphorylation of TbPIP39 at tyrosine 278 (Y278) increased upon CCA treatment of trypanosomes and was reversed by TbPTP1. TbPIP39 was present in the stumpy form, increased in abundance during differentiation, and was required for differentiation. The presence of wild-type or catalytically inactive TbPIP39 stimulated TbPTP1 activity in vitro, and this effect was abolished by treating the proteins with CCA. Therefore, TbPTP1 maintained the stumpy state by inhibiting TbPIP39, which, when active, promoted its own inactivation by enhancing the activity of TbPTP1. Immunofluorescence microscopy and subcellular fractionation indicated that TbPIP39 was present in glycosomes, which are trypanosomal organelles similar to peroxisomes where glycolysis occurs and which undergo remodeling during trypanosome differentiation. A mutant form of TbPIP39 that could not localize to glycosomes did not support differentiation. The authors propose that TbPTP1, which is a cytosolic protein associated with the cytoskeleton, has access to TbPIP39 only during its transit to the glycosome after synthesis and is locked in either the on or off state once it is sequestered in the glycosome. These two phosphatases therefore constitute a bistable switch in which TbPTP1 dephosphorylates TbPIP39 to maintain the stumpy form, but exposure of the trypanosome to CCA relieves this repression, thus allowing active TbPIP39 to reach the glycosome, where it is protected from inactivation.

B. Szöor, I. Ruberto, R. Burchmore, K. R. Matthews, A novel phosphatase cascade regulates differentiation in Trypanosoma brucei via a glycosomal signaling pathway. Genes Dev. 24, 1306–1316 (2010). [Abstract] [Full Text]

Citation: A. M. VanHook, Bistable Trypanosome Switch. Sci. Signal. 3, ec186 (2010).


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