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Advances in understanding bacterial outer-membrane biogenesis

Nature Reviews Microbiology volume 4, pages 57–66 (2006)Cite this article

Key Points

  • The outer membrane (OM) of Gram-negative bacteria functions as a selective barrier that controls the influx and efflux of solutes, a property that is crucial for bacterial survival in different environments. The OM of Escherichia coli has been extensively studied and serves as the paradigm for Gram-negative species. Although biochemical and microscopic data on the molecular composition and structure of the E. coli OM have been available since the 1950s, it is only relatively recently that details on the lipopolysaccharide (LPS) and OM protein (OMP) assembly factors have been obtained.

  • The components of the outer membrane — OMPs, phospholipids and LPS — are synthesized in the cytoplasm and at the inner leaflet of the inner membrane (IM), respectively, and must be transported to the OM after synthesis.

  • Translocation across the IM occurs through the SecYEG translocon for OMPs. LPS is transported from the inner leaflet to the outer leaflet of the IM by the ATP-binding cassette transporter MsbA, which 'flips' LPS from one leaflet to the other. In E. coli, MsbA might also transport phospholipids across the IM.

  • Three possible scenarios for transit of proteins, phospholipids and LPS from the inner membrane across the periplasm to the OM have been considered — vesicle-mediated transit, transit at contact sites between the two membranes and chaperone-mediated transit — and each of these scenarios is considered in turn.

  • Researchers have used a variety of genetic screens to identify OM-assembly mutants. Although such screens have greatly increased our knowledge of the biosynthesis of components of the OM and how they are transported across the IM, they generate too many unrelated mutations to be of use in identifying factors involved in OM assembly.

  • In our laboratory, we have identified additional criteria that, if used, can help identify leaky mutants that are truly defective in OM biogenesis; these criteria, and the experiments that led to their delineation, are discussed. In addition, we have identified a novel application of chemical genetics — chemical conditionality — that we have used to successfully identify a factor required for OM assembly, YfgL. YfgL was found to exist in a multiprotein complex with the β-barrel OMP YaeT and two OM lipoproteins, YfiO and NlpB.

  • Although the discovery of the YfgL-containing multiprotein complex is a key step towards understanding the assembly of the OM, it is likely that additional factors involved in the assembly of the OM remain to be identified. The chemical-conditionality screening technique described here could be used to identify these factors, and could also be useful in identifying factors involved in the assembly of other organelles.

Abstract

The outer membrane of Gram-negative bacteria such as Escherichia coli serves as a protective barrier that controls the influx and efflux of solutes. This allows the bacteria to inhabit several different, and often hostile, environments. The assembly of the E. coli outer membrane has been difficult to study using traditional genetic and biochemical methods, and how all its components reach the outer membrane after being synthesized in the cytoplasm and cytoplasmic membrane, how they are assembled in an environment that is devoid of an obvious energy source, and how assembly proceeds without disrupting the integrity of this essential cellular structure are all fundamental questions that remain unanswered. Here, we review the new approaches that have led to the recent discovery of components of the machinery involved in the biogenesis of this distinctive cellular organelle.

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Figure 1: General structure of the Escherichia coli cell envelope.
Figure 2: Biogenesis of the outer membrane.
Figure 3: A chemical genetic approach to identify outer-membrane-assembly factors.
Figure 4: The pathway of chemical sensitivity.

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Acknowledgements

This work was supported by grants from the National Institute of General Medical Sciences.

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Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Princeton, 08544, New Jersey, USA

    Natividad Ruiz & Thomas J. Silhavy

  2. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, 01238, Massachusetts, USA

    Daniel Kahne

  3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Daniel Kahne

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DATABASES

Entrez

Escherichia coli

Neisseria meningitidis

Glossary

Organelle

A structure in a cell that carries out a specific function.

Two-component system

Protein pair involved in signal transduction in which the sensor is a histidine kinase, the effector is a response regulator, and the signalling is based on the phosphotransfer between these two components.

Lipid A

A phosphorylated glucosamine disaccharide acylated with fatty acids.

Core oligosaccharide

Part of lipopolysaccharide that is attached to lipid A and that contains 3-deoxy-d-manno-oct-2-ulosonic acid, heptoses and hexoses.

SecYEG translocon

Inner-membrane protein complex composed of SecY, SecE and SecG through which newly synthesized envelope proteins are transported into or across the inner membrane.

ABC transporter

An inner-membrane protein or multiprotein complex that translocates substrates across the inner membrane using ATP as the energy source.

Leaky mutant

A cell with a defective outer membrane that allows the entry of molecules and/or the loss of periplasmic constituents.

Envelope stress responses

Signal-transduction pathways that sense an extracytoplasmic stress and upregulate components that combat it.

Suppressor mutation

A mutation that reverses a phenotype caused by a different mutation.

Spontaneous mutant

A mutant obtained without the use of mutagens such as transposons or chemicals.

Chemical genetics

Genetic approach that uses small molecules to elicit a phenotypic change.

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Ruiz, N., Kahne, D. & Silhavy, T. Advances in understanding bacterial outer-membrane biogenesis. Nat Rev Microbiol 4, 57–66 (2006). https://doi.org/10.1038/nrmicro1322

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