Abstract
The outer membrane (OM) of Gram-negative bacteria provides the cell with a formidable barrier that excludes external threats. The two major constituents of this asymmetric barrier are lipopolysaccharide (LPS) found in the outer leaflet, and glycerophospholipids (GPLs) in the inner leaflet. Maintaining the asymmetric nature and balance of LPS to GPLs in the OM is critical for bacterial viability. The biosynthetic pathways of LPS and GPLs are well characterized, but unlike LPS transport, how GPLs are translocated to the OM remains enigmatic. Understanding this aspect of cell envelope biology could provide a foundation for new antibacterial therapies. Here, we report that YhdP and its homologues, TamB and YdbH, members of the “AsmA-like” family, are critical for OM integrity and necessary for proper GPL transport to the OM. The absence of the two largest AsmA-like proteins (YhdP and TamB) leads to cell lysis and antibiotic sensitivity, phenotypes that are rescued by reducing LPS synthesis. We also find that yhdP, tamB double mutants shed excess LPS through outer membrane vesicles, presumably to maintain OM homeostasis when normal anterograde GPL transport is disrupted. Moreover, a yhdP, tamB, ydbH triple mutant is synthetically lethal, but if GPL transport is partially restored by overexpression of YhdP, the cell shape adjusts to accommodate increased membrane content as the cell accumulates GPLs in the IM. Our results therefore suggest a model in which “AsmA-like” proteins transport GPLs to the OM, and when hindered, changes in cell shape and shedding of excess LPS aids in maintaining OM asymmetry.
Highlights
The cell envelope of Gram-negative bacteria, such as Escherichia coli, provides a formidable barrier that protects the cell from toxic molecules under a wide range of environmental conditions [1]
We report that members of the “AsmA-like” family, YhdP, TamB, and YdbH contribute to the outer membrane (OM) barrier by aiding in GPL transport and are critical for antibiotic resistance
Unlike the symmetrical inner membrane (IM) that consist of glycerophospholipids (GPLs), the OM is asymmetrical with GPLs found in the inner leaflet and the glycolipid lipopolysaccharide (LPS) located in the outer leaflet [2]
Summary
The cell envelope of Gram-negative bacteria, such as Escherichia coli, provides a formidable barrier that protects the cell from toxic molecules under a wide range of environmental conditions [1]. The cell envelope encompasses a symmetrical membrane bilayer known as the inner membrane (IM), an aqueous periplasmic space, and a secondary outer membrane (OM) that surrounds the peptidoglycan layer. Unlike the symmetrical IM that consist of glycerophospholipids (GPLs), the OM is asymmetrical with GPLs found in the inner leaflet and the glycolipid lipopolysaccharide (LPS) located in the outer leaflet [2]. LPS is divided into three major components: the conserved lipid A domain, the core oligosaccharide, and the distal O-antigen [3]. Charged phosphates of LPS facilitate cross-bridging with divalent cations promoting strong lateral interactions between adjacent LPS molecules resulting in a selective permeability barrier [3]
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