The lipopolysaccharide transport (Lpt) machinery: A nonconventional transporter for lipopolysaccharide assembly at the outer membrane of Gram-negative bacteria

Sperandeo, Paola; Martorana, Alessandra M.; Polissi, Alessandra

doi:10.1074/jbc.r117.802512

Cited by 74 publications

(76 citation statements)

References 90 publications

(114 reference statements)

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“…A long hydrophobic groove has been observed in other LT protein complexes. The Lpt complex comprises seven components, named LptA–G, and it transfers lipopolysaccharides (LPSs) across the periplasm in bacteria . In the Lpt complex, LptA, LptC, and LptD are equipped with β‐jellyroll domains, which stack upon each other to form a hydrophobic pathway, that enable LPS molecules to cross the periplasm.…”

Section: Proposed Mechanism Of Phospholipid Transfer Mediated By Atg2mentioning

confidence: 99%

“…The Lpt complex comprises seven components, named LptA-G, and it transfers lipopolysaccharides (LPSs) across the periplasm in bacteria. 50 In the Lpt complex, LptA, LptC, and LptD are equipped with β-jellyroll domains, which stack upon each other to form a hydrophobic pathway, that enable LPS molecules to cross the periplasm. The ERMES complex comprises four subunits (Mdm12, Mdm35, Mdm10, and Mmm1) and mediates phospholipid transfer between mitochondria and the ER.…”

Section: Proposed Mechanism Of Phospholipid Transfer Mediated By Atg2mentioning

confidence: 99%

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Atg2: A novel phospholipid transfer protein that mediates de novo autophagosome biogenesis

Osawa

Noda

2019

Protein Science

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The degradation of cytoplasmic components via autophagy is crucial for intracellular homeostasis. In the process of autophagy, a newly synthesized isolation membrane (IM) is developed to sequester degradation targets and eventually the IM seals, forming an autophagosome. One of the most poorly understood autophagy‐related proteins is Atg2, which is known to localize to a contact site between the edge of the expanding IM and the exit site of the endoplasmic reticulum (ERES). Recent advances in structural and biochemical analyses have been applied to Atg2 and have revealed it to be a novel multifunctional protein that tethers membranes and transfers phospholipids between them. Considering that Atg2 is essential for the expansion of the IM that requires phospholipids as building blocks, it is suggested that Atg2 transfers phospholipids from the ERES to the IM during the process of autophagosome formation, suggesting that lipid transfer proteins can mediate de novo organelle biogenesis.

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Section: Proposed Mechanism Of Phospholipid Transfer Mediated By Atg2mentioning

confidence: 99%

Section: Proposed Mechanism Of Phospholipid Transfer Mediated By Atg2mentioning

confidence: 99%

Atg2: A novel phospholipid transfer protein that mediates de novo autophagosome biogenesis

Osawa

Noda

2019

Protein Science

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“…All these processes occur in the inner membrane and require the activities of membrane-embedded proteins that participate in various key steps of lipid A-core and OAg assembly (Valvano, 2011). LPS export from the inner to the outer membrane and the proper insertion of LPS in the outer leaflet of the outer membrane require Lpt proteins, which form a trans-cell envelope multiprotein complex spaning the inner and outer membranes (Okuda et al, 2016;Sperandeo et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Escherichia coli and Pseudomonas aeruginosa lipopolysaccharide O‐antigen ligases share similar membrane topology and biochemical properties

Ruan

Feria

Hamad

et al. 2018

Molecular Microbiology

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WaaL is an inner membrane glycosyltransferase that catalyzes the transfer of O-antigen polysaccharide from its lipid-linked intermediate to a terminal sugar of the lipid A-core oligosaccharide, a conserved step in lipopolysaccharide biosynthesis. Ligation occurs at the periplasmic side of the bacterial cell membrane, suggesting the catalytic region of WaaL faces the periplasm. Establishing the membrane topology of the WaaL protein family will enable understanding its mechanism and exploit it as a potential antimicrobial target. Applying oxidative labeling of native methionine/cysteine residues, we previously validated a topological model for Escherichia coli WaaL, which differs substantially from the reported topology of the Pseudomonas aeruginosa WaaL, derived from the analysis of truncated protein reporter fusions. Here, we examined the topology of intact E. coli and P. aeruginosa WaaL proteins by labeling engineered cysteine residues with the membrane-impermeable sulfhydryl reagent polyethylene glycol maleimide (PEG-Mal). The accessibility of PEG-Mal to targeted engineered cysteine residues in both E. coli and P. aeruginosa WaaL proteins demonstrates that both ligases share similar membrane topology. Further, we also demonstrate that P. aeruginosa WaaL shares similar functional properties with E. coli WaaL and that E. coli WaaL may adopt a functional dimer conformation.

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“…The biogenesis of LPS, which includes its biosynthesis and transport, is a process involving many proteins, well conserved across Gram‐negative bacteria and absent in eukaryotic cells, thus representing an ideal target for the development of novel antibacterials with the potential to be effective against multi‐resistant strains.…”

Section: Targeting Lps Biogenesis Pathway For the Discovery Of Novel mentioning

confidence: 99%

“…[22] Treating Gram-negative infections is therefore becoming increasingly difficut not only because of their intrinsinc resistance to antibiotics, but also because the alarming increase of multiresistant strains is progressively reducing our arsenal of efficacious molecules. The biogenesis of LPS, which includes its biosynthesis and transport, is a process involving many proteins, well conserved across Gram-negative bacteria and absent in eukaryotic cells, [11,14,19,46] thus representing an ideal target for the development of novel antibacterials with the potential to be effective against multi-resistant strains.…”

Section: Implication Of Having An Lps-coated Outer Membrane As Interfmentioning

confidence: 99%

Fat Matters for Bugs: How Lipids and Lipid Modifications Make the Difference in Bacterial Life

Sperandeo

Polissi

Fabiani

2019

Euro J Lipid Sci & Tech

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Lipids are building blocks of biological membranes in the three domains of life and are endowed with several important biological functions. Lipopolysaccharide (LPS) is a peculiar glycolipid that represents the hallmark of the cell envelope of Gram‐negative bacteria, a group comprising several important human pathogens. The presence of LPS in the outer membrane (OM) of Gram‐negative bacteria correlates not only with the intrinsic resistance of this group of bacteria toward several antibiotics currently in use, but also with the worrisome increase in antibiotic resistance that is depleting the arsenal of efficacious molecules to cure bacterial infections. LPS consists of a conserved internal moiety decorated by a more variable distal unit. Several modifications occur at the canonical LPS structure during bacterial infection which are exploited by the microorganism to co‐evolve with the host thus evading its immune system. This viewpoint article discusses the current knowledge on LPS biogenesis and modification systems and their consequences on recognition by immune cells and antimicrobial resistance. It also discusses how knowledge on LPS biogenesis can be exploited to develop molecules able to dismantle the Gram‐negative protective barrier and to interfere with the interaction with the mammalian host. Practical Applications: Antibiotic resistance is a major threat for human health leading to inefficacy of many antibiotics to treat infectious diseases. Resistance to antibiotics causes around 25 000 deaths per year in the European Union alone and 700 000 deaths per year globally. This results in an increase of 1.5 billion euros per year in healthcare costs and productivity losses for illness. Gram‐negative bacteria are intrinsically resistant to many antibiotics, due to their LPS‐coated cell surface that protects them from the environment. LPS is sensed by the host immune system as a signal of bacterial infection, moreover bacteria exploit the complexity of LPS modifications to modulate the host immune response and eventually escape it. A deep understanding of the molecular mechanisms underlying LPS biogenesis, including the physico‐chemical and biological consequences of its lipid modifications, will be instrumental to develop novel antibiotic treatments aimed at dismantling the Gram‐negative bacteria barrier and restoring drug sensitivity. The hallmark of Gram‐negative bacteria is the presence of an asymmetric outer membrane (OM) surrounding the cytoplasmic membrane (inner membrane, IM), whose outer leaflet is made by lipopolysaccharide (LPS). A layer of peptidoglycan (PG) is sandwiched in between. LPS endows the bacteria with increased resistance to many antibiotics and is the first line of interaction with the host cell immune system. Chemical modifications of the canonical LPS structure determine different stimulatory effects of the immune response and allow the bacteria to escape from the killing action of effector molecules such as antimicrobial peptides.

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The lipopolysaccharide transport (Lpt) machinery: A nonconventional transporter for lipopolysaccharide assembly at the outer membrane of Gram-negative bacteria

Cited by 74 publications

References 90 publications

Atg2: A novel phospholipid transfer protein that mediates de novo autophagosome biogenesis

Atg2: A novel phospholipid transfer protein that mediates de novo autophagosome biogenesis

Escherichia coli and Pseudomonas aeruginosa lipopolysaccharide O‐antigen ligases share similar membrane topology and biochemical properties

Fat Matters for Bugs: How Lipids and Lipid Modifications Make the Difference in Bacterial Life

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