An envelope stress response governs long-chain fatty acid metabolism via a small RNA to maintain redox homeostasis in Escherichia coli

Long-chain fatty acids (LCFAs) are a tremendous source of energy for several bacteria but are complex to use because they induce redox stress. We previously showed that LCFA degradation impedes oxidative protein folding in the Escherichia coli envelope, an issue that arises due to the insufficiency of ubiquinone, a lipid-soluble electron carrier in the electron transport chain (ETC). To maintain redox homeostasis, E. coli activates the CpxAR two-component system; however, the nature of feedback imparted by this envelope stress response (ESR) remained unknown. Here, we show that contrary to the well-recognized remedial mode of Cpx restoring envelope integrity by upregulating protein quality control factors, in LCFA-grown cells, it uses a preventive measure to maintain homeostasis. Cpx increases ubiquinone availability for oxidative protein folding by suppressing LCFA metabolism and directly increasing ubiquinone levels. Further, rather than using its conventional mode of imparting regulation via CpxR working as a transcriptional regulator, during LCFA metabolism, Cpx mainly uses its non-coding arm to counteract envelope redox stress. The Cpx-regulated small RNA CpxQ represses fad genes involved in LCFA transport and β-oxidation, downregulates components of glyoxylate shunt, gluconeogenesis, and ETC, and increases ubiquinone content. Corroborating with its role in repressing LCFA metabolism and maintaining redox homeostasis, CpxQ overexpression impairs growth of E. coli in LCFAs and CpxQ deletion renders LCFA-grown E. coli hypersensitive to a thiol agent. Our foremost work studying the interconnection between LCFA metabolism, redox stress, and ESR in E. coli provides a rationale for investigating similar networks in other LCFA-utilizing bacteria.