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Envelope stress responses: balancing damage repair and toxicity


The Gram-negative envelope is a complex structure that consists of the inner membrane, the periplasm, peptidoglycan and the outer membrane, and protects the bacterial cell from the environment. Changing environmental conditions can cause damage, which triggers the envelope stress responses to maintain cellular homeostasis. In this Review, we explore the causes, both environmental and intrinsic, of envelope stress, as well as the cellular stress response pathways that counter these stresses. Furthermore, we discuss the damage to the cell that occurs when these pathways are aberrantly activated either in the absence of stress or to an excessive degree. Finally, we review the mechanisms whereby the σE response constantly acts to prevent cell death caused by highly toxic unfolded outer membrane proteins. Together, the recent work that we discuss has provided insights that emphasize the necessity for proper levels of stress response activation and the detrimental consequences that can occur in the absence of proper regulation.

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The authors thank members of the Silhavy laboratory for productive discussions. In addition, they thank the National Institute of General Medical Sciences for funding (grant R32-GM118024 to T.J.S.).

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Nature Reviews Microbiology thanks S. Ades, A. Darwin and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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A.M.M. and T.J.S. researched data for the article, wrote the article and reviewed and/or edited the manuscript before submission.

Correspondence to Thomas J. Silhavy.

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Outer membrane ß-barrel proteins

(OMPs). Integral membrane proteins of the outer membrane with a β-barrel structure.

Efflux pumps

Proton-motive-force-driven or ATP-driven transporters that transport toxic molecules out of the cell.

Bile salts

Molecules that are produced as part of bile that function as detergents and help the nutritional absorption of lipids.


A set of genes that are transcriptionally regulated by a regulator.

β-Barrel assembly machinery

(BAM). An outer membrane protein complex that inserts outer membrane proteins into the outer membrane.


A small RNA that decreases the translation of some outer membrane β-barrel proteins as well as other targets.


A small RNA that decreases the translation of some outer membrane proteins as well as other targets.


A highly abundant outer membrane lipoprotein that crosslinks the outer membrane to the peptidoglycan layer.

Two-component system

A signalling system comprising an inner membrane sensor histidine kinase that phosphorylates a response regulator that functions as a transcriptional control factor.


A periplasmic chaperone that helps prevent the misfolding and aggregation of newly synthesized outer membrane β-barrel proteins.


A transcriptional regulator that is possibly involved in the utilization of β-glucosides.


A transcriptional regulator that controls genes related to pH homeostasis and efflux.


A transcription factor involved in the switch between a planktonic and an adhered lifestyle.


A transcriptional regulator with poorly defined function.

Proton motive force

(PMF). The build-up of protons in the periplasm generated by the electron transport chain used to generate ATP as well as directly drive some transport processes.


A sigma factor involved in controlling the expression of nitrogen-regulated and nitrogen-related genes.


An outer membrane protein involved in the secretion of substrates through the outer membrane.


An antibiotic that targets peptidoglycan biosynthesis by preventing recycling of the isoprenoid lipid carrier used to assemble peptidoglycan monomers.


An antibiotic that targets transcriptional elongation.

FtsZ ring

An assembly of a ring of FtsZ proteins that represents the earliest characterized step in cell division and determines the location of the septum.


An L,D-transpeptidase that catalyses meso-diaminopimelyl → meso-diaminopimelyl peptide bond crosslinks in peptidoglycan.


A phosphatidylglycerophosphate synthase that catalyses the first committed step in the biosynthesis of acidic phospholipids.


A metalloproteinase inhibitor that can inhibit the activity of the protease RseP.

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Fig. 1: Overview of envelope stress responses.
Fig. 2: Constitutive activation of stress responses is harmful.
Fig. 3: Toxicity of unfolded outer membrane β-barrel proteins.