Supplementary MaterialsData_Sheet_1. to envelope stress in enteric bacteria that are exposed to iron-limited environments, which are rich in envelope-damaging compounds and conditions. encode several tripartite multidrug efflux systems, many of which use the same outer membrane channel, TolC (Li et al., 2015). Decades of research have shown that TolC is required for the efflux of a wide variety of dyes, detergents, Lodoxamide Tromethamine and antibiotics. However, there is a growing body of evidence to suggest that TolC is also required for the secretion of endogenously produced metabolites. Intra- and extracellular concentrations of cysteine, indole, porphyrins, and siderophores are affected by loss of TolC or TolC-dependent efflux pumps (Bleuel et al., 2005; Tatsumi and Wachi, 2008; Wiriyathanawudhiwong et al., 2009; Horiyama and Nishino, 2014). Furthermore, accumulation of several metabolites increases expression of the TolC-dependent AcrAB multidrug efflux system as a compensatory mechanism to increase metabolite secretion (Helling et al., 2002; Ruiz and Levy, 2014). Blocking metabolite secretion by mutating or TolC-dependent efflux systems increases sensitivity to cysteine, the siderophore enterobactin, and intermediates of heme biosynthesis, suggesting that metabolite accumulation is toxic (Tatsumi and Wachi, 2008; Wiriyathanawudhiwong et al., 2009; Lodoxamide Tromethamine Vega and Young, 2014). In support of this hypothesis, numerous cellular stress responses are activated in bacteria lacking (Rosner and Martin, 2009; Guest and Raivio, 2016a), including the Cpx envelope stress response. Current evidence suggests that the Cpx envelope stress response functions to monitor and maintain the biogenesis of inner membrane protein and proteins complexes (Vogt and Raivio, 2012; Raivio, 2014; Visitor et al., 2017). This response can be controlled by an average two-component sign Lodoxamide Tromethamine transduction program comprising the internal membrane-bound sensor CpxA as well as the cytoplasmic response regulator CpxR (Weber and Silverman, 1988; Dong et al., 1993). In the current presence of an inducing sign, CpxA autophosphorylates as well as the phosphate can be then used in CpxR (Raivio and Silhavy, 1997). Once phosphorylated, CpxR features like a transcription element to activate the expression of genes associated with protein biogenesis and inner membrane integrity (Danese et al., 1995; Danese and Silhavy, 1997, 1998; Pogliano et al., 1997; Raivio et al., 2000, 2013; Price and Raivio, 2009), and repress the expression of genes that encode macromolecular envelope-localized protein complexes (McEwen and Silverman, 1980; Dorel et al., 1999; Hernday et al., 2004; MacRitchie et al., 2008; Vogt et al., 2010; Acosta et al., 2015; Guest et al., 2017). Once homeostasis is achieved, CpxA functions as a phosphatase to dephosphorylate CpxR and attenuate the response (Raivio and Silhavy, 1997). Inhibition of efflux activates the Cpx response in several gram-negative bacteria, including (Slamti and Rabbit Polyclonal to Myb Waldor, 2009; Santos et al., 2010; Rinker et al., 2011; Rosner and Martin, 2013; Acosta et al., 2014; Taylor et al., 2014), and is the most conserved Cpx-inducing cue identified to date. Clues as to how impaired efflux activates the Cpx response have come from studies in lacking the TolC-dependent efflux system VexGH is suppressed when are grown in the presence of iron, suggesting that the metabolite responsible for activation of the Cpx response is produced when iron is limiting (Acosta et al., 2014). In a subsequent study, this metabolite was identified as the catechol siderophore vibriobactin (Kunkle et al., 2017). This study also found that the Cpx response is no longer activated in an efflux mutant when bacteria are grown anaerobically or when succinate dehydrogenase of the electron transport chain is disrupted. As such, it has been proposed that accumulation of vibriobactin activates the Cpx response via the electron transport chain. It.