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J. Biol. Chem., Vol. 280, Issue 42, 35238-35246, October 21, 2005

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Distinct 3'-Untranslated Region Elements Regulate Stage-specific mRNA Accumulation and Translation in Leishmania^*

From the Infectious Diseases Research Center, Centre Hospitalier de l'Université Laval Research Center of Laval University and Department of Medical Biology, Faculty of Medicine, Laval University, Quebec G1V 4G2, Canada

We recently characterized a large developmentally regulated gene family in Leishmania encoding the amastin surface proteins. While studying the regulation of these genes, we identified a region of 770 nucleotides (nt) within the 2055-nt 3'-untranslated region (3'-UTR) that regulates stage-specific gene expression at the level of translation. An intriguing feature of this 3'-UTR regulatory region is the presence of a 450-nt element that is highly conserved among several Leishmania mRNAs. Here we show, using a luciferase reporter system and polysome profiling experiments, that the 450-nt element stimulates translation initiation of the amastin mRNA in response to heat shock, which is the main environmental change that the parasite encounters upon its entry into the mammalian host. Deletional analyses depicted a second region of 100 nucleotides located at the 3'-end of several amastin transcripts, which also activates translation in response to elevated temperature. Both 3'-UTR regulatory elements act in an additive manner to stimulate amastin mRNA translation. In addition, we show that acidic pH encountered in the phagolysosomes of macrophages, the location of parasitic differentiation, triggers the accumulation of amastin transcripts by a distinct mechanism that is independent of the 450-nt and 100-nt elements. Overall, these important findings support the notion that stage-specific post-transcriptional regulation of the amastin mRNAs in Leishmania is complex and involves the coordination of distinct mechanisms controlling mRNA stability and translation that are independently triggered by key environmental signals inducing differentiation of the parasite within macrophages.

Received for publication, July 11, 2005 , and in revised form, August 19, 2005.

^* This work was supported in part by the Canadian Institutes of Health Research (CIHR), Operating Grant MOP-12182, (to B. P.). 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.

¹ Holds a Canada Graduate Scholarships Doctoral Award from CIHR.

² A recipient of Deutscher Akademischer Austausch Dienst fellowship.

³ Recipients of Fonds de Recherche en Santé du Québec (FRSQ) fellowships.

⁴ A member of a CIHR group on host-pathogen interactions (GR-14500) and an FRSQ Senior Scholar and a Burroughs Wellcome Fund New Investigator in Molecular Parasitology. To whom correspondence should be addressed: Infectious Diseases Research Center, Centre Hospitalier de l'Université Laval Research Center, Centre Hospitalier Universitaire de Quebec, 2705 Laurier Blvd., Quebec G1V4G2, Canada. Tel.: 418-654-2705; Fax: 418-654-2715; E-mail: barbara.papadopoulou{at}crchul.ulaval.ca.

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