FapR, a Bacterial Transcription Factor Involved in Global Regulation of Membrane Lipid Biosynthesis in Bacillus subtilis

SCHUJAMN GE, PAOLETTI L, DE MENDOZA D.

Baveno, Italia

Conferencia; International Conference on Functional Genomics of Gram-Positive Microorganisms; 2003

One of the most daunting challenges in biology is elucidating the mechanisms by which cells sense and respond to changes in the biosynthesis of essential building blocks that support a majority of cellular activities. Among the critical metabolic changes that occur during various conditions in all living cells are fluctuations in the biosynthesis of fatty acids. In all organisms, fatty acids and their derivatives are essential components of membranes, are important sources of metabolic energy, and are important effectors molecules that regulate metabolism. Due to the essential roles that fatty acids have within the cell, the complex processes that govern the synthesis of these compounds must be regulated in such a manner as to allow the cell to adapt quickly to changes in the cell cycle or to environmental stress. Here we describe the identification and purification from Bacillus subtilis of a transcription factor, FapR, that controls the expression of many genes involved in fatty acids and phospholipid metabolism (the fap regulon). Expression of this fap regulon is influenced by antibiotics that specifically inhibit the fatty acid biosynthetic pathway. We show that FapR negatively regulates fap expression, and that the effects of antibiotics on fap expression are mediated by FapR. Disruption of fapR alters membrane fatty acids composition, and fapR mutant cells become extremely cold sensitive. This novel transcriptional regulator is also found in many other Gram-positive bacteria, many of which are known human pathogens. We further show that decreasing the cellular levels of malonyl-CoA, an essential molecule for fatty acid elongation, inhibits expression of the fap regulon and that this effect is FapR-dependent. Our results indicate that control of FapR by the cellular pools of malonyl-CoA provides a mechanism for sensing the status of fatty acid biosynthesis and to adjust the expression of the fap regulon accordingly. In toto, our results provide evidence for a novel mechanism of global control of membrane biogenesis in Gram-positive bacteria, in which the FapR regulator couples the status of fatty acid biosynthesis in cells with the expression of genes involved in lipid metabolism.