HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: fj.06-6818comv1 21/3/720    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oberholzer, M. Articles by Seebeck, T. Search for Related Content PubMed PubMed Citation Articles by Oberholzer, M. Articles by Seebeck, T.

The Trypanosoma brucei cAMP phosphodiesterases TbrPDEB1 and TbrPDEB2: flagellar enzymes that are essential for parasite virulence

Michael Oberholzer^*,1, Gabriela Marti^*, Mario Baresic^*, Stefan Kunz^*, Andrew Hemphill and Thomas Seebeck^*,2

^* Institute of Cell Biology and

Institute of Parasitology, University of Bern, Bern, Switzerland

²Correspondence: Institute of Cell Biology, Baltzerstrasse 4, CH-3012 Bern, Switzerland. E-mail: thomas.seebeck{at}izb.unibe.ch

Cyclic nucleotide specific phosphodiesterases (PDEs) are pivotal regulators of cellular signaling. They are also important drug targets. Besides catalytic activity and substrate specificity, their subcellular localization and interaction with other cell components are also functionally important. In contrast to the mammalian PDEs, the significance of PDEs in protozoal pathogens remains mostly unknown. The genome of Trypanosoma brucei, the causative agent of human sleeping sickness, codes for five different PDEs. Two of these, TbrPDEB1 and TbrPDEB2, are closely similar, cAMP-specific PDEs containing two GAF-domains in their N-terminal regions. Despite their similarity, these two PDEs exhibit different subcellular localizations. TbrPDEB1 is located in the flagellum, whereas TbrPDEB2 is distributed between flagellum and cytoplasm. RNAi against the two mRNAs revealed that the two enzymes can complement each other but that a simultaneous ablation of both leads to cell death in bloodstream form trypanosomes. RNAi against TbrPDEB1 and TbrPDEB2 also functions in vivo where it completely prevents infection and eliminates ongoing infections. Our data demonstrate that TbrPDEB1 and TbrPDEB2 are essential for virulence, making them valuable potential targets for new PDE-inhibitor based trypanocidal drugs. Furthermore, they are compatible with the notion that the flagellum of T. brucei is an important site of cAMP signaling.—Oberholzer, M., Marti, G., Baresic, M., Kunz, S., Hemphill, A., Seebeck, T. The Trypanosoma brucei cAMP phosphodiesterases TbrPDEB1 and TbrPDEB2: flagellar enzymes that are essential for parasite virulence.

Key Words: African sleeping sickness • PDE inhibitor • cytokinesis • life cycle stages • paraflagellar rod structure

This article has been cited by other articles:

				S. Griffiths, N. Portman, P. R. Taylor, S. Gordon, M. L. Ginger, and K. Gull RNA Interference Mutant Induction In Vivo Demonstrates the Essential Nature of Trypanosome Flagellar Function during Mammalian Infection Eukaryot. Cell, July 1, 2007; 6(7): 1248 - 1250. [Abstract] [Full Text] [PDF]