Border Control: Regulating LPS Biogenesis

The outer membrane (OM) is a defining feature of Gram-negative bacteria that serves as a permeability barrier and provides rigidity to the cell. Critical to OM function is establishing and maintaining an asymmetrical bilayer structure with phospholipids in the inner leaflet and the complex glycolipid lipopolysaccharide (LPS) in the outer leaflet. Cells ensure this asymmetry by regulating the biogenesis of lipid A, the conserved and essential anchor of LPS. Here we review the consequences of disrupting the regulatory components that control lipid A biogenesis, focusing on the rate-limiting step performed by LpxC. Dissection of these processes provides critical insights into bacterial physiology and potential new targets for antibiotics able to overcome rapidly spreading resistance mechanisms. Lipopolysaccharide (LPS) is found in most Gram-negative bacteria and is critical for outer membrane (OM) barrier function and maintaining cell rigidity.Gram-negative bacteria precisely regulate LPS levels as imbalances are lethal: too much LPS appears to disrupt inner-membrane integrity while too little weakens the OM.In Escherichia coli, LPS levels are regulated by the YciM/FtsH protease complex, which degrades the enzyme that catalyzes the first committed step in lipid A biogenesis, LpxC.Factors in multiple cellular compartments regulate activity of the YciM/FtsH protease complex in response to changes in LPS levels, including the essential inner-membrane protein YejM, the outer-membrane phospholipase PldA, and the lipid A biosynthetic intermediate lipid A disaccharide in the cytoplasm.