Transcriptional regulation of lipid biosynthesis in mycobacteria.

GAGO, G.; MONDINO, SONIA; GRAMAJO, H

Paris

Congreso; EMBO Conference: Tuberculosis 2012: Biology, Pathogenesis, intervention strategies.; 2012

EMBO

Transcriptional regulation of lipid biosynthesis in mycobacteria  Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB) in humans, continues to be a major health problem worldwide. Mycolic acids, one of the most important lipids of the outer membrane of mycobacteria, have been largely associated with bacterial virulence and antibiotic resistance and its biosynthesis pathway is one of the main targets for TB treatment. Biosynthesis of mycolic acids involves two structural distinct fatty acid synthase systems, FAS-I and FAS-II, which should work in a finely coordinate manner to keep lipid homeostasis tightly regulated. The main purpose of our studies is to understand how mycobacteria exert this exquisite control over the biosynthesis of their membrane lipids and find out the key components of the regulatory network that control fatty acid and mycolic acid biosynthesis at the transcriptional level. Since fatty acid biosynthesis is essential and energetically expensive, organisms have developed homeostatic mechanisms that maintain the concentration of lipids tightly regulated. Our pioneer studies demonstrated that in M. smegmatis and in M. tuberculosis, the expression of the fasII operon is regulated at the transcriptional level by MabR. This protein binds to an operator sequence present in the fasII promoter region, modulating in this way the biosynthesis of mycolic acids. Interestingly, overexpression of MabR not only affects the expression of fasII genes but also of fas, providing strong evidences of the existence of a sophisticated regulatory network involved in the coordinate regulation of the two mycobacterial FAS systems at the transcriptional level. Here, we present the in vivo and in vitro characterization of FasR, a new regulatory protein that specifically binds pfas to regulate the de novo fatty acid biosynthesis in mycobacteria. We also present evidences that long-chain acyl-CoAs are the effector molecules that coordinate the expression of the two FAS systems at the transcriptional level. A better understanding of this complex process of regulation of lipid homeostasis in mycobacteria will greatly contribute to the development of new strategies to control this disease, including the design or identification of compounds that could deregulate fatty acid biosynthesis and induce bacterial death.