Date Published: January 11, 2016
Publisher: Public Library of Science
Author(s): Amanda J. Martinot, Mary Farrow, Lu Bai, Emilie Layre, Tan-Yun Cheng, Jennifer H. Tsai, Jahangir Iqbal, John W. Annand, Zuri A. Sullivan, M. Mahmood Hussain, James Sacchettini, D. Branch Moody, Jessica C. Seeliger, Eric J. Rubin, Helena Ingrid Boshoff.
Mycobacterium tuberculosis (Mtb) mutants lacking rv1411c, which encodes the lipoprotein LprG, and rv1410c, which encodes a putative efflux pump, are dramatically attenuated for growth in mice. Here we show that loss of LprG-Rv1410 in Mtb leads to intracellular triacylglyceride (TAG) accumulation, and overexpression of the locus increases the levels of TAG in the culture medium, demonstrating a role of this locus in TAG transport. LprG binds TAG within a large hydrophobic cleft and is sufficient to transfer TAG from donor to acceptor membranes. Further, LprG-Rv1410 is critical for broadly regulating bacterial growth and metabolism in vitro during carbon restriction and in vivo during infection of mice. The growth defect in mice is due to disrupted bacterial metabolism and occurs independently of key immune regulators. The in vivo essentiality of this locus suggests that this export system and other regulators of metabolism should be considered as targets for novel therapeutics.
Tuberculosis continues to be a major global health threat.Mycobacterium tuberculosis (Mtb) is estimated to infect 2 billion people worldwide, or one-third of the world’s population . Despite its clinical importance, key aspects of tuberculosis (TB) pathogenesis are still not understood, including predictors of whether exposure will lead to active versus latent disease. Only 5% of exposed individuals will go on to develop active disease, whereas the remaining 95% will develop latent disease but remain susceptible to reactivation . Therefore, Mtb is able to survive during periods of reduced growth and has the capacity to regrow rapidly.
Mycobacteria, and Actinomycetes in general, are unique not only in their capacity to synthesize and store large quantities of TAG, but also in their ability to catabolize TAG as an energy source during starvation [19,53] . TAG accumulates within lipid droplets in the bacterial cytoplasm [42,55] and is associated with slow growth and antibiotic tolerance (52). TAG in the form of lipid droplets provides energy via β-oxidation of the acyl chains [45,56] and TAG seems to serve a structural role as a major component of the outer leaflet of the outer membrane . Like PDIM, TAG can also serve as a sink to alleviate the accumulation of potentially toxic propionyl-CoA [46,57]. Here we show loss of LprG and Rv1410 disrupts steady-state levels of intracellular TAG in Mtb. This could result in multiple cellular defects, consistent with the numerous roles that TAG is proposed to play in mycobacterial physiology and metabolism.