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J. Biol. Chem., Vol. 279, Issue 52, 54494-54501, December 24, 2004

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Growth Phase Regulation of the Main Folate Transporter of Leishmania infantum and Its Role in Methotrexate Resistance^*

Dave Richard, Philippe Leprohon, Jolyne Drummelsmith, and Marc Ouellette, A Burroughs Wellcome Fund scholar in molecular parasitology and the holder of a Canada research chair in antimicrobial resistance¶

From the Centre de Recherche en Infectiologie du Centre de Recherche du Centre Hospitalier and Division de Microbiologie, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada

The protozoan parasite Leishmania relies on the uptake of folate and pterin from the environment to meet its nutritional requirements. We show here that a novel gene (folate transporter 1 (FT1)) deleted in a Leishmania infantum methotrexate-resistant mutant corresponds to the main folate transporter (K_m, 410 nM). FT1 was established as the main folate transporter by both gene transfection and by targeted gene deletion. Modulation of the expression of FT1 by these manipulations altered the susceptibility of Leishmania cells to methotrexate. Folate transport was stage-regulated with higher activity in the logarithmic phase and less in the stationary phase. FT1 fused to green fluorescent protein led to the observation that FT1 was located in the plasma membrane in the logarithmic phase but was retargeted to an intracellular organelle followed by a degradation of the protein in stationary phase. Leishmania has several folate transporters with different characteristics, and the growth stage-related activity of at least one transporter is regulated post-translationally.

Received for publication, August 12, 2004 , and in revised form, September 13, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY577522.

^* This work was supported in part by the Canadian Institutes for Health Research (CIHR) (to M. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a studentship from CIHR.

Recipient of a postdoctoral fellowship from the CIHR.

^¶ To whom correspondence should be addressed: Centre de Recherche en Infectiologie, CHUQ, pavillon CHUL, 2705 boul. Laurier, Ste-Foy, Québec G1V 4G2, Canada. Tel.: 418-654-2705; Fax: 418-654-2715; E-mail: Marc.Ouellette{at}crchul.ulaval.ca.

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