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The Trypanosoma brucei cAMP phosphodiesterases TbrPDEBl and TbrPDEB2: flagellar enzymes that are essential for parasite virulence
Author(s) -
Oberholzer Michael,
Marti Gabriela,
Baresic Mario,
Kunz Stefan,
Hemphill Andrew,
Seebeck Thomas
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6818com
Subject(s) - trypanosoma brucei , flagellum , biology , virulence , subcellular localization , phosphodiesterase , microbiology and biotechnology , rna interference , cytoplasm , enzyme , genetics , biochemistry , rna , gene
Cyclic nucleotide specific phosphodiesterases (PDEs) are pivotal regulators of cellular signaling. They are also important drug targets. Besides catalytic activity and substrate specificity, their subcel‐lular 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, TbrPDEBl and TbrPDEB2, are closely similar, cAMP‐specific PDEs containing two GAF‐do‐mains 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 Tbr‐PDEB1 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. FASEB J. 21, 720–731 (2007)