An ABC transport system that maintains lipid asymmetry in the Gram-negative outer membrane

Malinverni, Juliana C.; Silhavy, Thomas J.

doi:10.1073/pnas.0903229106

Cited by 430 publications

(693 citation statements)

References 45 publications

(48 reference statements)

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“…VacJ has been characterized as an outer membrane protein associated to an ABC transporter system in other organisms, such as E. coli and Shigella flexneri , in which it has been proposed to be involved in the maintenance of outer membrane stability in the presence of membrane disruptors such as SDS (Carpenter et al, 2014; Malinverni & Silhavy, 2009). Its deletion has been shown to increase permeability of the outer membrane (Malinverni & Silhavy, 2009) and increase the formation of vesicles in E. coli and other gram‐negative bacteria (Roier et al, 2016). In P. aeruginosa , a VacJ homolog has been described to play a role in antibiotic resistance.…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide identification of tolerance mechanisms toward p‐coumaric acid in Pseudomonas putida

Calero

Jensen

Bojanovič

et al. 2017

Biotech & Bioengineering

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The soil bacterium Pseudomonas putida KT2440 has gained increasing biotechnological interest due to its ability to tolerate different types of stress. Here, the tolerance of P. putida KT2440 toward eleven toxic chemical compounds was investigated. P. putida was found to be significantly more tolerant toward three of the eleven compounds when compared to Escherichia coli. Increased tolerance was for example found toward p‐coumaric acid, an interesting precursor for polymerization with a significant industrial relevance. The tolerance mechanism was therefore investigated using the genome‐wide approach, Tn‐seq. Libraries containing a large number of miniTn5‐Km transposon insertion mutants were grown in the presence and absence of p‐coumaric acid, and the enrichment or depletion of mutants was quantified by high‐throughput sequencing. Several genes, including the ABC transporter Ttg2ABC and the cytochrome c maturation system (ccm), were identified to play an important role in the tolerance toward p‐coumaric acid of this bacterium. Most of the identified genes were involved in membrane stability, suggesting that tolerance toward p‐coumaric acid is related to transport and membrane integrity.

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Section: Discussionmentioning

confidence: 99%

Genome‐wide identification of tolerance mechanisms toward p‐coumaric acid in Pseudomonas putida

Calero

Jensen

Bojanovič

et al. 2017

Biotech & Bioengineering

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“…Bacterial GPL are synthesized on the inner leaflet of the IM by defined biosynthetic mechanisms (16). However, unlike lipid A, which is enzymatically flipped and transported to the OM by specialized protein machinery (17), our current understanding of the mechanism of GPL transport to the OM remains rudimentary by comparison (12), and specific regulation of OM GPL has not been demonstrated. Therefore, we explored the hypothesis that the S. Typhimurium PhoPQ virulence system regulates OM GPL content.…”

Section: Significancementioning

confidence: 99%

“…Upon membrane damage, inner-leaflet GPL molecules are hypothesized to flip into the OM outer leaflet to form what are predicted to be symmetrical lipid microdomains (1,10). In addition to PagP, many Gram-negative bacteria also possess a highly conserved OM phospholipase A (OMPLA) that has broad substrate specificity and hydrolyzes GPL within the OM outer leaflet to maintain bilayer asymmetry during replication (11,12). In addition to OMPLA, a dedicated system for the uptake and reacylation of the sn-1 lysophospholipids exists, and its function is linked to an acyl-acyl carrier protein on the cytoplasmic surface of the inner membrane (IM) (12,13).…”

mentioning

confidence: 99%

“…In addition to PagP, many Gram-negative bacteria also possess a highly conserved OM phospholipase A (OMPLA) that has broad substrate specificity and hydrolyzes GPL within the OM outer leaflet to maintain bilayer asymmetry during replication (11,12). In addition to OMPLA, a dedicated system for the uptake and reacylation of the sn-1 lysophospholipids exists, and its function is linked to an acyl-acyl carrier protein on the cytoplasmic surface of the inner membrane (IM) (12,13). Therefore, wholesale GPL transport and flipping is intrinsic to rapid restorative membrane repair.…”

mentioning

confidence: 99%

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PhoPQ regulates acidic glycerophospholipid content of the Salmonella Typhimurium outer membrane

Dalebroux¹,

Matamouros²,

Whittington

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

141

172

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Significance The outer membrane (OM) of Gram-negative bacteria is composed of lipopolysaccharide (LPS) and glycerophospholipids (GPLs). Environmental regulation of LPS promotes bacterial resistance to host cationic antimicrobial peptides by altering surface charge and hydrophobicity. This work demonstrates that pathogenic Salmonella coordinately regulate GPL and LPS through the PhoPQ regulatory proteins and the OM palmitoyltransferase enzyme PagP. The broad conservation of PhoPQ and PagP in bacteria suggests that environmental regulation of OM GPL may be a conserved stress-response strategy for antimicrobial resistance. Improved understanding of OM GPL synthesis, transport, and modification could lead to new therapies that target the bacterial OM barrier.

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“…Mla proteins are present in all compartments of the cell envelope and facilitate retrograde phospholipid transport from the OM back to the IM (15). MlaA is the lipoprotein component that interacts with OmpC in the OM (16) and is thought to remove PLs from the outer leaflet of the OM and shuttle them to MlaC, the soluble periplasmic component.…”

mentioning

confidence: 99%

Disruption of lipid homeostasis in the Gram-negative cell envelope activates a novel cell death pathway

Sutterlin

Shi

May

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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160

197

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Gram-negative bacteria balance synthesis of the outer membrane (OM), cell wall, and cytoplasmic contents during growth via unknown mechanisms. Here, we show that a dominant mutation (designated mlaA*, maintenance of lipid asymmetry) that alters MlaA, a lipoprotein that removes phospholipids from the outer leaflet of the OM of Escherichia coli, increases OM permeability, lipopolysaccharide levels, drug sensitivity, and cell death in stationary phase. Surprisingly, single-cell imaging revealed that death occurs after protracted loss of OM material through vesiculation and blebbing at celldivision sites and compensatory shrinkage of the inner membrane, eventually resulting in rupture and slow leakage of cytoplasmic contents. The death of mlaA* cells was linked to fatty acid depletion and was not affected by membrane depolarization, suggesting that lipids flow from the inner membrane to the OM in an energy-independent manner. Suppressor analysis suggested that the dominant mlaA* mutation activates phospholipase A, resulting in increased levels of lipopolysaccharide and OM vesiculation that ultimately undermine the integrity of the cell envelope by depleting the inner membrane of phospholipids. This novel cell-death pathway suggests that balanced synthesis across both membranes is key to the mechanical integrity of the Gram-negative cell envelope.

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An ABC transport system that maintains lipid asymmetry in the Gram-negative outer membrane

Cited by 430 publications

References 45 publications

Genome‐wide identification of tolerance mechanisms toward p‐coumaric acid in Pseudomonas putida

Genome‐wide identification of tolerance mechanisms toward p‐coumaric acid in Pseudomonas putida

PhoPQ regulates acidic glycerophospholipid content of the Salmonella Typhimurium outer membrane

Disruption of lipid homeostasis in the Gram-negative cell envelope activates a novel cell death pathway

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