Interaction between Polyketide Synthase and Transporter Suggests Coupled Synthesis and Export of Virulence Lipid in M. tuberculosis

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Abstract
Virulent mycobacteria utilize surface-exposed polyketides to interact with host cells, but the mechanism by which these hydrophobic molecules are transported across the cell envelope to the surface of the bacteria is poorly understood. Phthiocerol dimycocerosate (PDIM), a surface-exposed polyketide lipid necessary for Mycobacterium tuberculosis virulence, is the product of several polyketide synthases including PpsE. Transport of PDIM requires MmpL7, a member of the MmpL family of RND permeases. Here we show that a domain of MmpL7 biochemically interacts with PpsE, the first report of an interaction between a biosynthetic enzyme and its cognate transporter. Overexpression of the interaction domain of MmpL7 acts as a dominant negative to PDIM synthesis by poisoning the interaction between synthase and transporter. This suggests that MmpL7 acts in complex with the synthesis machinery to efficiently transport PDIM across the cell membrane. Coordination of synthesis and transport may not only be a feature of MmpL-mediated transport in M. tuberculosis, but may also represent a general mechanism of polyketide export in many different microorganisms. Pathogenic microbes have developed sophisticated strategies to evade the human immune system and establish infection. Mycobacterium tuberculosis, the causative agent of tuberculosis, exports a wide array of lipid virulence factors to the cell surface and into host cells, where they can interact with the host immune system. A strategy to combat M. tuberculosis infections may be to interfere with the bacterium's ability to make and secrete these lipids. In the authors' efforts to understand this process, they have found that synthesis and export of a key lipid virulence factor are coupled. They propose that the synthesis and transport proteins form a complex that promotes efficient lipid export. The coordination of lipid synthesis and export, analogous to co-translational translocation of secreted proteins, may be a general mechanism employed by many different microorganisms to actively transport hydrophobic molecules from cells.