Loss of cardiolipin and porins bypasses the essentiality of the sigma E cell envelope stress response in <i>Escherichia coli</i>

The Gram-negative cell envelope is composed of an inner and outer membrane, each with different lipid compositions. The inner membrane is predominantly made up of phosphatidylglycerol, phosphatidylethanolamine, and cardiolipin, while the outer membrane contains the same lipids but has a predominantly lipopolysaccharide composition in the outer leaflet. The outer membrane forms a permeability barrier that blocks the entry of toxins and antibiotics; however, it is decorated with outer membrane proteins that allow nutrient uptake and the efflux of intracellular toxins. In <i>Escherichia coli,</i> the σ^E stress response is essential for viability but is upregulated when disruptions to outer membrane protein biogenesis occurs. Here, we used a high-throughput genetic screen to identify genetic interactions with the genes responsible for cardiolipin biosynthesis. We demonstrate that the σ^E stress response is not essential in a mutant lacking cardiolipin and the major outer membrane protein OmpC. This mutant also became more resistant to batimastat, a selective inhibitor of RseP that causes a lethal decrease in σ^E activity in <i>E. coli</i>. Finally, we reveal that the toxicity associated with decreased σ^E activity can be relieved by treatment with an inhibitor of the Sec translocon, which translocates outer membrane proteins across the inner membrane. We conclude that the loss of cardiolipin suppresses Sec activity, reducing the level of misfolded outer membrane proteins in the periplasm, thereby relieving the essential nature of the σ^E stress response.IMPORTANCEThe process of building the Gram-negative bacterial cell envelope is complex and requires careful coordination of many different pathways. Because of its essential role in maintaining cell viability, the cell envelope is an important target for new antibiotic treatments. The membranes that make up the cell envelope contain three major lipids, but the precise role of these lipids and how they influence the coordination of the different cell envelope pathways is not well understood. Our data indicate that when the synthesis of one of these lipids is abolished, coordination of cell envelope biosynthesis is dysregulated. Importantly, an essential regulatory mechanism for controlling the response to disruption of the cell envelope becomes non-essential. These findings provide new insight into cell envelope biogenesis that could be harnessed for developing antimicrobial strategies.