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Flotillin scaffold activity contributes to type VII secretion system assembly in Staphylococcus aureus.

ABSTRACT: Scaffold proteins are ubiquitous chaperones that promote efficient interactions between partners of multi-enzymatic protein complexes; although they are well studied in eukaryotes, their role in prokaryotic systems is poorly understood. Bacterial membranes have functional membrane microdomains (FMM), a structure homologous to eukaryotic lipid rafts. Similar to their eukaryotic counterparts, bacterial FMM harbor a scaffold protein termed flotillin that is thought to promote interactions between proteins spatially confined to the FMM. Here we used biochemical approaches to define the scaffold activity of the flotillin homolog FloA of the human pathogen Staphylococcus aureus, using assembly of interacting protein partners of the type VII secretion system (T7SS) as a case study. Staphylococcus aureus cells that lacked FloA showed reduced T7SS function, and thus reduced secretion of T7SS-related effectors, probably due to the supporting scaffold activity of flotillin. We found that the presence of flotillin mediates intermolecular interactions of T7SS proteins. We tested several small molecules that interfere with flotillin scaffold activity, which perturbed T7SS activity in vitro and in vivo. Our results suggest that flotillin assists in the assembly of S. aureus membrane components that participate in infection and influences the infective potential of this pathogen.

SUBMITTER: Mielich-Suss B

PROVIDER: S-EPMC5718613 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Flotillin scaffold activity contributes to type VII secretion system assembly in Staphylococcus aureus.

Mielich-Süss Benjamin B Wagner Rabea M RM Mietrach Nicole N Hertlein Tobias T Marincola Gabriella G Ohlsen Knut K Geibel Sebastian S Lopez Daniel D

PLoS pathogens 20171122 11

Scaffold proteins are ubiquitous chaperones that promote efficient interactions between partners of multi-enzymatic protein complexes; although they are well studied in eukaryotes, their role in prokaryotic systems is poorly understood. Bacterial membranes have functional membrane microdomains (FMM), a structure homologous to eukaryotic lipid rafts. Similar to their eukaryotic counterparts, bacterial FMM harbor a scaffold protein termed flotillin that is thought to promote interactions between p ...[more]

PMID: 29166667

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Project description:BackgroundType VII protein secretion (T7SS) is a specialised system for excreting extracellular proteins across bacterial cell membranes and has been associated with virulence in Staphylococcus aureus. The genetic diversity of the ess locus, which encodes the T7SS, and the functions of proteins encoded within it are poorly understood.ResultsWe used whole genome sequence data from 153 isolates representative of the diversity of the species to investigate the genetic variability of T7SS across S. aureus. The ess loci were found to comprise of four distinct modules based on gene content and relative conservation. Modules 1 and 4, comprising of the 5' and 3' modules of the ess locus, contained the most conserved clusters of genes across the species. Module 1 contained genes encoding the secreted protein EsxA, and the EsaAB and EssAB components of the T7SS machinery, and Module 4 contained two functionally uncharacterized conserved membrane proteins. Across the species four variants of Module 2 were identified containing the essC gene, each of which was associated with a specific group of downstream genes. The most diverse module of the ess locus was Module 3 comprising a highly variable arrangement of hypothetical proteins. RNA-Seq was performed on representatives of the four Module 2 variants and demonstrated strain-specific differences in the levels of transcription in the conserved Module 1 components and transcriptional linkage Module 2, and provided evidence of the expression of genes the variable regions of the ess loci.ConclusionsThe ess locus of S. aureus exhibits modularity and organisational variation across the species and transcriptional variation. In silico analysis of ess loci encoded hypothetical proteins identified potential novel secreted substrates for the T7SS. The considerable variety in operon arrangement between otherwise closely related isolates provides strong evidence for recombination at this locus. Comparison of these recombination regions with each other, and with the genomes of other Staphylococcal species, failed to identify evidence of intra- and inter-species recombination, however the analysis identified a novel T7SS in another pathogenic staphylococci, Staphylococcus lugdunensis.

Dataset Information

Flotillin scaffold activity contributes to type VII secretion system assembly in Staphylococcus aureus.

Publications

Flotillin scaffold activity contributes to type VII secretion system assembly in Staphylococcus aureus.

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