Revisiting the Gram-Negative Lipoprotein Paradigm

LoVullo, Eric D.; Wright, Lori; Isabella, Vincent M.; Huntley, Jason F.; Pavelka, Martin S.

doi:10.1128/jb.02414-14

Cited by 61 publications

(85 citation statements)

References 58 publications

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“…LoVullo and colleagues confirmed this by constructing ⌬lnt deletion mutations in two different F. tularensis strains, including a human-pathogenic F. tularensis subsp. tular-ensis strain (5). The study further demonstrated that the known F. tularensis lipoprotein Tul4 (LpnA) shifts from a triacylated form in the wild-type strain to a diacylated form in the ⌬lnt background and that Tul4 and additional lipoproteins are still properly sorted to the OM in the ⌬lnt mutant.…”

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confidence: 67%

“…Interestingly, the Lol system of F. tularensis lacks a gene for LolE, which in E. coli heterodimerizes with LolC to form the membrane component of the ABC transporter complex. Comparison of the lol genes present in various Gram-negative bacteria revealed that the absence of lolE is not unique to Francisella, but instead was found in more than half of the bacterial genomes they analyzed (5). Based on protein sequence analysis, LoVullo et al concluded that the single LolC present in bacteria such as Francisella spp.…”

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confidence: 99%

“…Due to the high cost associated with lipoprotein mislocalization, Gram-negative bacteria have evolved a conserved mechanism for the processing and sorting of these molecules, to ensure they correctly reach their final destination. In this issue of the Journal of Bacteriology, LoVullo et al (5) challenge the current paradigm for lipoprotein processing and sorting in Gram-negative bacteria.…”

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confidence: 99%

“…LoVullo et al (5) hypothesized that the Lol pathway of Francisella must contain some alternative functionality that allows it to recognize diacylated lipoproteins. Interestingly, the Lol system of F. tularensis lacks a gene for LolE, which in E. coli heterodimerizes with LolC to form the membrane component of the ABC transporter complex.…”

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confidence: 99%

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A More Flexible Lipoprotein Sorting Pathway

Chahales

Thanassi

2015

J Bacteriol

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Lipoprotein biogenesis in Gram-negative bacteria occurs by a conserved pathway, each step of which is considered essential. In contrast to this model, LoVullo and colleagues demonstrate that the N-acyl transferase Lnt is not required in Francisella tularensis or Neisseria gonorrhoeae. This suggests the existence of a more flexible lipoprotein pathway, likely due to a modified Lol transporter complex, and raises the possibility that pathogens may regulate lipoprotein processing to modulate interactions with the host. Lipoproteins are a diverse class of multifunctional, membraneassociated molecules. Their contributions to the bacterial cell range from essential processes, such as maintaining envelope architecture and stability, to assisting with and mediating hostpathogen interactions (1-3). Lipoproteins constitute a significant fraction of the outer membrane (OM) of Gram-negative bacteria and are recognized as a pathogen-associated molecular pattern by host cells (3,4). Due to the high cost associated with lipoprotein mislocalization, Gram-negative bacteria have evolved a conserved mechanism for the processing and sorting of these molecules, to ensure they correctly reach their final destination. In this issue of the Journal of Bacteriology, LoVullo et al. (5) challenge the current paradigm for lipoprotein processing and sorting in Gram-negative bacteria.As with the majority of proteins destined for the periplasm or OM, the N terminus of a newly synthesized lipoprotein contains a cleavable signal peptide, which typically directs the preprolipoprotein to the Sec general secretory pathway for translocation across the cytoplasmic or inner membrane (IM) to the periplasm ( Fig. 1) (2, 6). The C-terminal end of the signal peptide contains a 4-amino-acid lipobox motif, terminating with an invariant cysteine in the ϩ1 position (the N terminus of the mature lipoprotein). This cysteine provides the acylation site and is required for lipoprotein processing. In addition, residues in the ϩ2, ϩ3, and ϩ4 positions adjacent to the lipobox cysteine act as signals that determine whether the lipoprotein is sorted to the OM (the default pathway) or remains in the IM (7,8). Finally, a flexible tethering sequence links the N-terminal processing and sorting determinants to the mature functional region of the protein (2).Following transport through the Sec translocon to the periplasm, the preprolipoprotein remains anchored to the IM by its N-terminal signal peptide (Fig. 1). Lgt, a preprolipoprotein diacylglyceryl transferase, catalyzes the addition of a diacylglyceride moiety to the sulfhydryl group of the ϩ1 cysteine, forming a prolipoprotein (9). Next, the prolipoprotein signal peptidase Lsp cleaves the Nterminal amide bond of the ϩ1 cysteine, releasing the signal peptide and leaving the lipoprotein anchored to the IM via its diacylated cysteine residue (10). With the ϩ1 cysteine amino group now accessible, the final processing step requires the N-acyl transferase Lnt to catalyze the linkage of an additional acyl chain to the free am...

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confidence: 67%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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A More Flexible Lipoprotein Sorting Pathway

Chahales

Thanassi

2015

J Bacteriol

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“…42 It is also possible that the presence of LolE permease, part of ABC transporter LolCDE, on E. coli contributed to resistance to this set of compounds, while the other Gram-negative F. tularensis was greatly inhibited. 43 In support of this, one group examining SMIs opted to use a strain of E. coli that has a shortened LPS, which renders it more permeable to SMIs. 44 This technique will be worth considering in future studies.…”

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confidence: 99%

Identification of inhibitors for single-stranded DNA-binding proteins in eubacteria

Glanzer

Endres

Byrne

et al. 2016

J. Antimicrob. Chemother.

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Objectives: The increasing threat of drug-resistant bacteria establishes a continuing need for the development of new strategies to fight infection. We examine the inhibition of the essential single-stranded DNA-binding proteins (SSBs) SSBA and SSBB as a potential antimicrobial therapy due to their importance in DNA replication, activating the SOS response and promoting competence-based mechanisms of resistance by incorporating new DNA.Methods: Purified recombinant SSBs from Gram-positive (Staphylococcus aureus and Bacillus anthracis) and Gram-negative (Escherichia coli and Francisella tularensis) bacteria were assessed in a high-throughput screen for inhibition of duplex DNA unwinding by small molecule inhibitors. Secondary electrophoretic mobility shift assays further validated the top hits that were then tested for MICs using in vitro assays. Results:We have identified compounds that show cross-reactivity in vitro, as well as inhibition of both F. tularensis and B. anthracis SSBA. Five compounds were moderately toxic to at least two of the four bacterial strains in vivo, including two compounds that were selectively non-toxic to human cells, 9-hydroxyphenylfluoron and purpurogallin. Three of the SSBA inhibitors also inhibited S. aureus SSBB in Gram-positive bacteria. Conclusions:Results from our study support the potential for SSB inhibitors as broad-spectrum antibacterial agents, with dual targeting capabilities against Gram-positive bacteria.

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Mycobacterium tuberculosis lipoproteins in virulence and immunity – fighting with a double‐edged sword

Becker

Sander

2016

FEBS Letters

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Bacterial lipoproteins are secreted membrane‐anchored proteins characterized by a lipobox motif. This lipobox motif directs post‐translational modifications at the conserved cysteine through the consecutive action of three enzymes: Lgt, LspA and Lnt, which results in di‐ or triacylated forms. Lipoproteins are abundant in all bacteria including Mycobacterium tuberculosis and often involved in virulence and immunoregulatory processes. On the one hand, disruption of the biosynthesis pathway of lipoproteins leads to attenuation of M. tuberculosis in vivo, and mycobacteria deficient for certain lipoproteins have been assessed as attenuated live vaccine candidates. On the other hand, several mycobacterial lipoproteins form immunodominant antigens which promote an immune response. Some of these have been explored in DNA or subunit vaccination approaches against tuberculosis. The immune recognition of specific lipoproteins, however, might also benefit long‐term survival of M. tuberculosis through immune modulation, while others induce protective responses. Exploiting lipoproteins as vaccines is thus a complex matter which requires deliberative investigation. The dual role of lipoproteins in the immunity to and pathogenicity of mycobacteria is discussed here.

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Revisiting the Gram-Negative Lipoprotein Paradigm

Cited by 61 publications

References 58 publications

A More Flexible Lipoprotein Sorting Pathway

A More Flexible Lipoprotein Sorting Pathway

Identification of inhibitors for single-stranded DNA-binding proteins in eubacteria

Mycobacterium tuberculosis lipoproteins in virulence and immunity – fighting with a double‐edged sword

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