Investigating the regulation of long chain fatty acid metabolism by the Cpx envelope stress response in Escherichia coli

Abstract

Long-chain fatty acids (LCFAs) represent a tremendous energy source for bacteria newlineincluding many pathogens; however, their utilization confers stress in bacteria. Using newlineEscherichia coli as a model, previous work from our lab showed that the oxidation of a newlinelarge number of reduced cofactors generated during LCFA metabolism increases electron newlineflow towards ubiquinone, a lipid-soluble electron carrier in the electron transport chain newline(ETC). Because ubiquinone also re-oxidizes the disulfide bond (DSB)-forming machinery newlinethat performs oxidative protein folding in the envelope, the outermost multi-layered newlinecompartment critical for cellular growth and viability, increased electron flow during newlineLCFA metabolism hampers the essential process of DSB formation, thereby compromising newlineenvelope redox balance. Notably, E. coli induces the CpxAR two-component system to newlinecounteract stress. The upregulation of envelope-localized chaperones and proteases is a newlinewell-recognized remedial mechanism by which Cpx restores cellular integrity. However, newlinemy work has identified Cpx as a global regulator of LCFA metabolism that uses a newlinepreventive measure to maintain envelope homeostasis in LCFA-grown cells; it facilitates newlineDSB formation by downregulating LCFA metabolism and increasing the oxidizing power newlineof ETC. Interestingly, contrary to its conventional mode of imparting regulation via CpxR newlineworking mainly as a transcriptional regulator, during LCFA metabolism, Cpx uses its non newlinecoding arm to counteract envelope redox stress. The Cpx-regulated small RNA (sRNA) newlineCpxQ i) represses fad genes involved in LCFA transport and and#61538;-oxidation, ii) downregulates newlinecomponents of the glyoxylate shunt, gluconeogenesis, and ETC, and iii) stabilizes another newlinesRNA OmrA, and both these sRNAs increase ubiquinone content. My work in E. coli newlinerevealing the interconnection between LCFA metabolism, redox stress, and envelope stress newlineresponse provides the rationale for investigating similar networks in other LCFA-utilizing newlinebacteria. newline