FasR, a novel class of transcriptional regulator, governs the activation of fatty acid biosynthesis genes in Streptomyces coelicolor

ARABOLAZA ANA, MATILDE D´ANGELO, SANTIAGO COMBA AND HUGO GRAMAJO

MOLECULAR MICROBIOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2010 vol. 78 p. 47 - 63

0950-382X

Membrane lipid homeostasis is essential for bacterialsurvival and adaptation to different environments.The regulation of fatty acid biosynthesis is thereforecrucial for maintaining the correct composition andbiophysical properties of cell membranes. Thisregulation implicates a biochemical control of keyenzymes and a transcriptional regulation of genesinvolved in lipid metabolism. In Streptomyces coelicolorwe found that control of lipid homeostasis isaccomplished, at least in part, through the transcriptionalregulation of fatty acid biosynthetic genes. Anovel transcription factor, FasR (SCO2386), controlsexpression of fabDHPF operon and lies immediatelyupstream of fabD, in a cluster of genes that is highlyconserved within actinomycetes. Disruption of fasRresulted in a mutant strain, with severe growthdefects and a delay in the timing of morphologicaland physiological differentiation. Expression of fabgenes was downregulated in the fasR mutant, indicatinga role for this transcription factor as an activator.Consequently, the mutant showed a significant dropin fatty acid synthase activity and triacylglycerideaccumulation. FasR binds specifically to a DNAsequence containing fabDHPF promoter region, bothin vivo and in vitro. These data provide the firstexample of positive regulation of genes encodingcore proteins of saturated fatty acid synthasecomplex.IntroductionIn all organisms, fatty acids and their derivatives areessential components of membranes, crucial source ofmetabolic energy and important effector molecules thatregulate metabolism. As a result of the essential role thatfatty acids play, the complex processes governing theirsynthesis are regulated so as to allow biological membranesto maintain a stable composition that is characteristicfor different organisms or tissues (DiRusso andNystrom, 1998; Dobrosotskaya et al., 2002; Rock andJackowski, 2002). Moreover, fatty acids are the mostenergetically expensive membrane lipid components tobe produced in the cell; thus, the regulation of their productionis tightly controlled to match growth rate (Zhangand Rock, 2009).Bacteria have evolved sophisticated mechanisms tofinely control expression of the genes responsible for theformation and degradation of fatty acids and to modifyexisting fatty acyl chains so as to adjust the biophysicalproperties of the fatty acids to maintain a stable membrane(Zhang and Rock, 2008). To date, the regulation offatty acid metabolism has been mainly studied in modelprokaryotes such as Escherichia coli (Rock and Cronan,1996; Cronan and Subrahmanyam, 1998; DiRusso andNystrom, 1998; Marrakchi et al., 2002; Zhang et al., 2002)and Bacillus subtilis (Schujman et al., 2003; Schujmanet al., 2006; Matsuoka et al., 2007). The Gram negative E.coli is an enteric g-proteobacterium that possesses mostlystraight-chain fatty acids. In this microorganism the globaltranscriptional regulator FadR, a member of the GntRfamily of regulators (Haydon and Guest, 1991), is principallyinvolved in the control of fatty acid degradation andthe cellular processes related to it (Haydon and Guest,1991; DiRusso et al., 1992). FadR negatively regulatesthe machinery required for fatty acid b-oxidation and isantagonized by long-chain acyl-CoAs (Rock and Cronan,1996; Cronan and Subrahmanyam, 1998; DiRusso andNystrom, 1998). Interestingly, this protein also regulates,in a positive manner, the synthesis of unsaturated fattyacids (Henry and Cronan, 1991; Campbell and Cronan,2001) by binding to the upstream regions of the promotersof fabB [3-ketoacyl-acyl carrier protein (ACP) synthase]Accepted 18 June