Transcriptional regulation of lipid homeostasis in mycobacteria

SALZMAN, VALENTINA; MONDINO, SONIA; SALA, CLAUDIA; COLE, STEWART; GAGO, GABRIELA; GRAMAJO, HUGO

MOLECULAR MICROBIOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2010 vol. 78 p. 64 - 77

0950-382X

Mycolic acids are major components of the cell envelope of mycobacteria, such as Mycobacterium tuberculosis, and play an important role in its architecture, impermeability and interaction with the environment. Synthesis of mycolic acids is carried out by two types of fatty acid synthases (FAS) working in concert: type I FAS, a multifunctional enzyme capable of de novo synthesis of medium-chain fatty acids, and type II FAS, responsible for their elongation. In this paper we report the identification and characterization of a novel transcriptional regulator (FasR), whose binding to the FAS-II promoter region was demonstrated in vitro and in vivo. Overexpression and knock-down studies in M. smegmatis revealed the repressor nature of FasR, with reduced amounts of FAS-II transcripts and fatty acids in the overproducing strain. Under these conditions, down-regulation of fas transcription was also observed, thereby suggesting the existence of crosstalk between the two FAS, mediated by FasR. Finally, the finding that a fasR knock-out mutant could only be obtained in a merodiploid strain of M. smegmatis, confirmed the predicted essentiality, thus implying an essential role for FasR in mycobacterial fatty acid metabolism.