Assimilation of fatty acids and cholesterol in Mycobacterium tuberculosis
Mycobacterium tuberculosis (Mtb) as a causative agent of human tuberculosis has successfully adapted to survive within the host for decades, and the bacterium’s ability to metabolize host-derived lipids (fatty acids and cholesterol) is thought to enable this persistence. Here we provide insights into previously unknown regulatory mechanisms of lipid assimilation in Mtb. Specifically, we identified a fatty acid transporter Mce1. We determined that previously uncharacterized protein Rv3723/LucA coordinates uptake of both fatty acids and cholesterol through its interaction with accessory subunits of Mce1 and Mce4, respectively. Rv3723/LucA or Mce accessory subunits provide stability to the lipid transporters by protecting from degradation with protease. Moreover, cholesterol and fatty acids imported into the cell send downstream signals to modulate assimilation of each other. Our results demonstrate that fatty acid and cholesterol import in Mtb is exquisitely coordinated through a network of proteins associated with Mce1 and Mce4. Additionally, to further define genes required for assimilation of fatty acids during macrophage infection, we employed an unbiased approach of genetic screen using metabolic labeling. We identified a number of genes with previously unknown link to lipid metabolism, and also determined that Mce1, Mce accessory protein OmamB and the ATPase MceG are required for import of fatty acids by Mtb inside the host. Elucidation of the mechanisms for lipid uptake in Mtb will help us understand key survival strategies of the pathogen, and identify new points of vulnerability for drug discovery.
cholesterol; fatty acids; LucA; macrophages; mce; tuberculosis; Biochemistry; Microbiology
Russell, David G.
Crane, Brian; Sondermann, Holger
Ph. D., Microbiology
Doctor of Philosophy
dissertation or thesis