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Molecular and Cellular Biology, May 2005, p. 3774-3783, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3774-3783.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

An Evolutionarily Conserved Coiled-Coil Protein Implicated in Polycystic Kidney Disease Is Involved in Basal Body Duplication and Flagellar Biogenesis in Trypanosoma brucei{dagger}

Gareth W. Morgan,1,{ddagger} Paul W. Denny,1,§ Sue Vaughan,2 David Goulding,1 Tim R. Jeffries,1,¶ Deborah F. Smith,1,|| Keith Gull,2 and Mark C. Field1*

Department of Biological Sciences, Imperial College, London,1 Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom2

Received 1 July 2004/ Returned for modification 10 August 2004/ Accepted 18 January 2005

Trypanosoma brucei is a flagellated protozoan with a highly polarized cellular structure. TbLRTP is a trypanosomal protein containing multiple SDS22-class leucine-rich repeats and a coiled-coil domain with high similarity to a mammalian testis-specific protein of unknown function. Homologues are present in a wide range of higher eukaryotes including zebra fish, where the gene product has been implicated in polycystic kidney disease. Western blot analysis and immunofluorescence with antibodies against recombinant TbLRTP indicate that the protein is expressed throughout the trypanosome life cycle and localizes to distal zones of the basal bodies. Overexpression and RNA interference demonstrate that TbLRTP is important for faithful basal body duplication and flagellum biogenesis. Expression of excess TbLRTP suppresses new flagellum assembly, while reduction of TbLRTP protein levels often results in the biogenesis of additional flagellar axonemes and paraflagellar rods that, most remarkably, are intracellular and fully contained within the cytoplasm. The mutant flagella are devoid of membrane and are often associated with four microtubules in an arrangement similar to that observed in the normal flagellar attachment zone. Aberrant basal body and flagellar biogenesis in TbLRTP mutants also influences cell size and cytokinesis. These findings demonstrate that TbLRTP suppresses basal body replication and subsequent flagellar biogenesis and indicate a critical role for the LRTP family of proteins in the control of the cell cycle. These data further underscore the role of aberrant flagellar biogenesis as a disease mechanism.

* Corresponding author. Present address: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom. Phone: 44-1223-333-734. Fax: 44-1223-333-346. E-mail: mcf34{at}cam.ac.uk.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Virology, The Wright-Fleming Institute, Faculty of Medicine, Imperial College, London, United Kingdom.

§ Present address: School for Health (Medicine), University of Durham, Stockton-on-Tees, United Kingdom.

Present address: Department of Cell Biology, Ludwig Institute for Cancer Research, Yale University, New Haven CT 00520-8002.

|| Present address: Department of Biology, University of York, York, United Kingdom.

Molecular and Cellular Biology, May 2005, p. 3774-3783, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3774-3783.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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