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Article contents

Leishmania donovani: proteasome-mediated down-regulation of methionine adenosyltransferase

Published online by Cambridge University Press:  03 August 2011

YOLANDA PÉREZ-PERTEJO
Affiliation:
Departamento de Farmacología y Toxicología (INTOXCAL), Universidad de León, Campus de Vegazana s/n; 24071 León, Spain
RAQUEL ÁLVAREZ-VELILLA
Affiliation:
Departamento de Farmacología y Toxicología (INTOXCAL), Universidad de León, Campus de Vegazana s/n; 24071 León, Spain
CARLOS GARCÍA ESTRADA
Affiliation:
Departamento de Farmacología y Toxicología (INTOXCAL), Universidad de León, Campus de Vegazana s/n; 24071 León, Spain
RAFAEL BALAÑA-FOUCE
Affiliation:
Departamento de Farmacología y Toxicología (INTOXCAL), Universidad de León, Campus de Vegazana s/n; 24071 León, Spain
ROSA M. REGUERA
Affiliation:
Departamento de Farmacología y Toxicología (INTOXCAL), Universidad de León, Campus de Vegazana s/n; 24071 León, Spain
Corresponding
E-mail address:

Summary

Methionine adenosyltransferase (MAT) is an important enzyme for metabolic processes, to the extent that its product, S-adenosylmethionine (AdoMet), plays a key role in trans-methylation, trans-sulphuration and polyamine synthesis. Previous studies have shown that a MAT-overexpressing strain of Leishmania donovani controls AdoMet production, keeping the intracellular AdoMet concentration at levels that are compatible with cell survival. This unexpected result, together with the fact that MAT activity and abundance changed with time in culture, suggests that different regulatory mechanisms acting beyond the post-transcriptional level are controlling this protein. In order to gain an insight into these mechanisms, several experiments were carried out to explain the MAT abundance during promastigote cell growth. Determination of MAT turnover in cycloheximide (CHX)-treated cultures resulted in a surprising 5-fold increase in MAT turnover compared to CHX-untreated cultures. This increase agrees with a stabilization of the MAT protein, whose integrity was maintained during culture. The presence of proteasome inhibitors, namely MG-132, MG-115, epoxomycin and lactacystin in the culture medium prevented MAT degradation in both MAT-overexpressing and ‘mock-transfected’ leishmanial strains. The role of the ubiquitin (Ub) pathway in MAT down-regulation was supported using immunoprecipitation experiments. Immunoprecipitated MAT cross-reacted with anti-Ub antibodies, which provides evidence of a proteasome-mediated down-regulation of the leishmanial MAT abundance.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2011

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