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Genes & Dev. 24 (12): 1306-1316

Copyright © 2010 by Cold Spring Harbor Laboratory Press.

A novel phosphatase cascade regulates differentiation in Trypanosoma brucei via a glycosomal signaling pathway

Balázs Szöor1,4, Irene Ruberto1, Richard Burchmore2,, and Keith R. Matthews1,3

1 Centre for Immunity, Infection, and Evolution, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT; United Kingdom;
2 Sir Henry Wellcome Proteomics Facility, University of Glasgow G12 8QQ, United Kingdom

Abstract: In the mammalian bloodstream, the sleeping sickness parasite Trypanosoma brucei is held poised for transmission by the activity of a tyrosine phosphatase, TbPTP1. This prevents differentiation of the transmissible "stumpy forms" until entry into the tsetse fly, whereupon TbPTP1 is inactivated and major changes in parasite physiology are initiated to allow colonization of the arthropod vector. Using a substrate-trapping approach, we identified the downstream step in this developmental signaling pathway as a DxDxT phosphatase, TbPIP39, which is activated upon tyrosine phosphorylation, and hence is negatively regulated by TbPTP1. In vitro, TbPIP39 promotes the activity of TbPTP1, thereby reinforcing its own repression, this being alleviated by the trypanosome differentiation triggers citrate and cis-aconitate, generating a potentially bistable regulatory switch. Supporting a role in signal transduction, TbPIP39 becomes rapidly tyrosine-phosphorylated during differentiation, and RNAi-mediated transcript ablation in stumpy forms inhibits parasite development. Interestingly, TbPIP39 localizes in glycosomes, peroxisome-like organelles that compartmentalize the trypanosome glycolytic reactions among other enzymatic activities. Our results invoke a phosphatase signaling cascade in which the developmental signal is trafficked to a unique metabolic organelle in the parasite: the glycosome. This is the first characterized environmental signaling pathway targeted directly to a peroxisome-like organelle in any eukaryotic cell.

Key Words: Glycosome • peroxisome • signal transduction • phosphatase • Trypanosoma brucei • differentiation

Received for publication November 26, 2009. Accepted for publication April 22, 2010.

3 Corresponding authors.

3E-MAIL keith.matthews{at}; FAX 44-131-651-3670.

4 E-MAIL Balazs.Szoor{at}; FAX 44-131-651-3670.

Article is online at

Supplemental material is available at

Controlling and Coordinating Development in Vector-Transmitted Parasites.
K. R. Matthews (2011)
Science 331, 1149-1153
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