The role of the dihydroxyacetone phosphate acyltransferase LmDAT in lipophosphoglycan synthesis, metacyclogenesis and autophagy in Leishmania major

Date

2007-06-28T16:12:46Z

Journal Title

Journal ISSN

Volume Title

Publisher

Kansas State University

Abstract

Glycerolipids are the most abundant lipids and are important constituents of various virulence factors in the protozoan parasite Leishmania. The dihydroxyacetone phosphate acyltransferase LmDAT catalyzes the first step of the ether, and possibly ester glycerolipid biosynthetic pathway. A L. major null mutant of LmDAT grew slowly, died rapidly during the stationary phase of growth, and more importantly, was attenuated in virulence in mice. The goal of this study was to determine the molecular basis responsible for the attenuated virulence. Western blot analysis revealed that the ∆lmdat/∆lmdat null mutant synthesized altered versions of the virulence factor lipophosphoglycans that were not released in the media, suggesting that its lipid anchor structure was altered. The ∆lmdat/∆lmdat strain differentiated into virulent metacyclics, but with lower efficiency compared to the wild type. Using the autophagosomal marker ATG8-GFP, the ∆lmdat/∆lmdat line produced twice as many autophagosomes as the wild type, suggesting that it is either defective in degradation of autophagosomes or that autophagy is simply induced. In conclusion, the attenuated virulence of ∆lmdat/∆lmdat may be explained by i) its inability to synthesize and release normal forms of lipophosphoglycan, ii) its inability to fully differentiate into virulent metacyclics, and iii) altered autophagy.

Description

Keywords

Leishmania major, Lipophosphoglycans, Dihydroxyacetone phosphate acyltransferase, Metacyclogenesis, Autophagy

Graduation Month

August

Degree

Master of Science

Department

Department of Biochemistry

Major Professor

Rachel Zufferey

Date

2007

Type

Thesis

Citation