Abstract
Latent infection with dormant Mycobacterium tuberculosis is one of the major reasons behind the emergence of drug-resistant strains of the pathogen worldwide. In its dormant state, the pathogen accumulates lipid droplets containing triacylglycerol synthesized from fatty acids derived from host lipids. In this study, we show that Rv1206 (FACL6), which is annotated as an acyl-CoA synthetase and resembles eukaryotic fatty acid transport proteins, is able to stimulate fatty acid uptake in E. coli cells. We show that purified FACL6 displays acyl-coenzyme A synthetase activity with a preference towards oleic acid, which is one of the predominant fatty acids in host lipids. Our results indicate that the expression of FACL6 protein in Mycobacterium tuberculosis is significantly increased during in vitro dormancy. The facl6-deficient Mycobacterium tuberculosis mutant displayed a diminished ability to synthesize acyl-coenzyme A in cell-free extracts. Furthermore, during in vitro dormancy, the mutant synthesized lower levels of intracellular triacylglycerol from exogenous fatty acids. Complementation partially restored the lost function. Our results suggest that FACL6 modulates triacylglycerol accumulation as the pathogen enters dormancy by activating fatty acids.
Highlights
Latent infection with Mycobacterium tuberculosis (Mtb) affects two billion people worldwide [1, 2]
We found that the FACL6 protein level was higher in Mtb cells in a dormant state than in Mtb cells in exponential growth phase
An open reading frame in Mtb has been suggested to encode a protein belonging to a family of Fatty acid transport proteins (FATPs) conserved from mycobacteria to humans [12]
Summary
Latent infection with Mycobacterium tuberculosis (Mtb) affects two billion people worldwide [1, 2]. In latent TB, Mtb is in a dormant state and becomes phenotypically tolerant to antibiotics, loses acid fastness and accumulates. Fatty acid transport proteins (FATPs) appear to be critical players in the transport of fatty acids across cell membranes [9,10,11]. The long-chain acyl coenzyme A synthetase (ACSL) activity of the FATP, which mediates the activation of fatty acids, probably plays an important role in regulating the rate of fatty acid uptake and in channeling the imported fatty acids between various metabolic processes within the cell [13, 14].
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