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Mechanism of outer membrane destabilization by global reduction of protein content

Author

Listed:
  • Irina V. Mikheyeva

    (Princeton University)

  • Jiawei Sun

    (Stanford University)

  • Kerwyn Casey Huang

    (Stanford University
    Stanford University School of Medicine
    Chan Zuckerberg Biohub)

  • Thomas J. Silhavy

    (Princeton University)

Abstract

The outer membrane (OM) of Gram-negative bacteria such as Escherichia coli is an asymmetric bilayer with the glycolipid lipopolysaccharide (LPS) in the outer leaflet and glycerophospholipids in the inner. Nearly all integral OM proteins (OMPs) have a characteristic β-barrel fold and are assembled in the OM by the BAM complex, which contains one essential β-barrel protein (BamA), one essential lipoprotein (BamD), and three non-essential lipoproteins (BamBCE). A gain-of-function mutation in bamA enables survival in the absence of BamD, showing that the essential function of this protein is regulatory. Here, we demonstrate that the global reduction in OMPs caused by BamD loss weakens the OM, altering cell shape and causing OM rupture in spent medium. To fill the void created by OMP loss, phospholipids (PLs) flip into the outer leaflet. Under these conditions, mechanisms that remove PLs from the outer leaflet create tension between the OM leaflets, which contributes to membrane rupture. Rupture is prevented by suppressor mutations that release the tension by halting PL removal from the outer leaflet. However, these suppressors do not restore OM stiffness or normal cell shape, revealing a possible connection between OM stiffness and cell shape.

Suggested Citation

  • Irina V. Mikheyeva & Jiawei Sun & Kerwyn Casey Huang & Thomas J. Silhavy, 2023. "Mechanism of outer membrane destabilization by global reduction of protein content," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40396-6
    DOI: 10.1038/s41467-023-40396-6
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    References listed on IDEAS

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    1. H. J. Snijder & I. Ubarretxena-Belandia & M. Blaauw & K. H. Kalk & H. M. Verheij & M. R. Egmond & N. Dekker & B. W. Dijkstra, 1999. "Structural evidence for dimerization-regulated activation of an integral membrane phospholipase," Nature, Nature, vol. 401(6754), pages 717-721, October.
    2. Enrique R. Rojas & Gabriel Billings & Pascal D. Odermatt & George K. Auer & Lillian Zhu & Amanda Miguel & Fred Chang & Douglas B. Weibel & Julie A. Theriot & Kerwyn Casey Huang, 2018. "The outer membrane is an essential load-bearing element in Gram-negative bacteria," Nature, Nature, vol. 559(7715), pages 617-621, July.
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