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Secretomics of the Staphylococcus aureus Type VII protein secretion system

ABSTRACT: The type VII protein secretion system (T7SS) is conserved across Staphylococcus aureus strains and plays important roles in virulence and interbacterial competition. To date only one T7SS substrate protein, encoded in a subset of strains, has been functionally characterized. Here, using an unbiased proteomic approach, we identify TspA as a further T7SS substrate.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Matthias Trost

LAB HEAD: Matthias Trost

PROVIDER: PXD011358 | Pride | 2020-09-28

REPOSITORIES: Pride

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			Action	DRS
	Maxquant-txt.zip	Other
	S.aureus_WT_1.raw	Raw
	S.aureus_WT_2.raw	Raw
	S.aureus_WT_3.raw	Raw
	S.aureus_WT_4.raw	Raw

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Publications

A membrane-depolarizing toxin substrate of the Staphylococcus aureus type VII secretion system mediates intraspecies competition.

Ulhuq Fatima R FR Gomes Margarida C MC Duggan Gina M GM Guo Manman M Mendonca Chriselle C Buchanan Grant G Chalmers James D JD Cao Zhenping Z Kneuper Holger H Murdoch Sarah S Thomson Sarah S Strahl Henrik H Trost Matthias M Mostowy Serge S Palmer Tracy T

Proceedings of the National Academy of Sciences of the United States of America 20200807 34

The type VII protein secretion system (T7SS) is conserved across Staphylococcus aureus strains and plays important roles in virulence and interbacterial competition. To date, only one T7SS substrate protein, encoded in a subset of S. aureus genomes, has been functionally characterized. Here, using an unbiased proteomic approach, we identify TspA as a further T7SS substrate. TspA is encoded distantly from the T7SS gene cluster and is found across all S. aureus strains as well ...[more]

PMID: 32769205

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The staphylococcal type VII secretion system impacts daptomycin sensitivity through controlling bacterial cell surface integrity

Project description:The human pathogen Staphylococcus aureus encodes a specialised type VII secretion system (T7SS), which plays an important role in bacterial virulence during infection. However, the functions the T7SS during infection and in bacterial physiology remain unclear. Here we demonstrate that S. aureus strains lacking the transporter EssC as well as the T7SS effectors, EsxC and EsxA were highly sensitive to the important last resort drug, daptomycin as well as other membrane-targeting antibiotics, including gramicidin and bithionol. To understand how T7SS mediates increased antibiotic sensitivity, we investigated the impact of T7SS on the staphylococcal cell envelope. Interestingly, T7SS mutants displayed decreased membrane fluidity with altered localisation of cell membrane proteins such as flotillin under normal growth conditions. LC/MS analysis showed different protein profiles in the mutant membrane preparations compared to the WT, suggesting that T7SS impacts membrane homeostasis. Scanning electron microscopy analysis demonstrated distinct cell surface morphologies for the T7SS mutants, with altered cell wall synthesis as well cell surface charge. In line with the increased negative surface charge, daptomycin binding was enhanced in the mutants, which demonstrated increased membrane permeability when treated with the drug. T7SS mutants were more sensitive to daptomycin during intracellular infection, and furthermore, in a murine skin infection model, esxC mutants survived less than the WT when treated with daptomycin. Thus, our data show that the T7SS impacts sensitivity of S. aureus to membrane-acting drugs such as daptomycin through modulation of cell membrane integrity, indicating its potential as a drug target

2024-04-19 | PXD047096 | Pride

Dynamics of protein expression reveals primary targets and secondary messengers of estrogen receptor signaling in MCF-7 breast cancer cells

Project description:Estrogen receptor-mediated proliferation of breast cancer cells is facilitated through expression of multiple primary target genes, products of which induce the secondary response to stimulation. To differentiate between the primary and secondary target genes of estrogen receptor signaling, we measured dynamics of protein expression induced by estradiol in MCF-7 breast cancer cells. Measurement of the global proteomic effects of estradiol by SILAC resulted in identification of 104 estradiol-regulated proteins, with only 41 corresponding genes having estrogen response elements (EREs). Selected reaction monitoring assays were used to validate 32 proteins and measure the dynamics of their expression within 72 hours upon estradiol stimulation and in the presence of 4-hydroxytamoxifen, thus confirming estrogen receptor-mediated signaling. Dynamics of protein expression revealed immediate early response proteins including TFF1 and CDK1 and delayed response proteins including CDK2 and NAB2. Presence or absence of EREs in the corresponding genes indicated early or delayed expression of proteins identified by SILAC. Finally, we measured accurate dynamics of estradiol-induced protein expression in the sub-network of primary and secondary targets of estrogen receptor. Interestingly, since NAB2 protein is also a repressor of EGR3-induced transcription, siRNA-mediated silencing of NAB2 resulted in the over-expression of some EGR3-induced proteins, such as ITGA2. To conclude, quantitative proteomics revealed secondary targets of estrogen receptor signaling potentially overlooked by genome-wide profiling of EREs and provided dynamics of protein expression in the network of transcription factors with a negative feedback loop.

2016-04-14 | PXD002797 | Pride

The type VII secretion system protects Staphylococcus aureus against host-specific fatty acids

Project description:The Staphylococcus aureus type VII secretion system (T7SS) exports several proteins that are pivotal for bacterial virulence. The mechanisms underlying T7SS-mediated staphylococcal survival during infection are nevertheless unclear. Here we show that EsxC, a small secreted effector implicated in bacterial persistence, contributes to S. aureus membrane architecture and fluidity. Interestingly, isogenic mutants lacking EsxC, T7SS effectors (EsxA or EsxB), and the membrane-bound EssC are more sensitive to killing by the host-specific fatty acid, linoleic acid (LA), compared to the wild-type. We demonstrate that LA induces more cell membrane damage in the T7SS mutants, although they do not bind differentially to LA. Membrane lipid profiles show that T7SS mutants are also less able to incorporate LA into their membrane phospholipids. Proteomics analyses of wild-type and mutant cell fractions reveal that, in addition to compromising membranes, T7SS defects readily induce bacterial stress and hamper their response to LA challenge. Together, our findings indicate that T7SS is crucial for S. aureus membrane integrity and homeostasis, which is critical when bacteria encounter antimicrobial fatty acids.

2021-09-08 | PXD013081 | Pride

Comaprison of the phagosome proteome of bone marrow-derived macrophages and RAW264.7

Project description:Macrophages are important immune cells operating at the forefront of innate immunity by taking up foreign particles and microbes through phagocytosis. The RAW 264.7 cell line is commonly used for experiments in the macrophage and phagocytosis field. However, little is known how its functions compare to primary macrophages. Here, we have performed an in-depth proteomics characterisation of phagosomes from RAW 264.7 and bone marrow-derived macrophages by quantifying more than 2500 phagosomal proteins. Our data indicates that there are significant differences for a large number of proteins including important receptors such as mannose receptor 1 and Siglec-1.

2015-02-10 | PXD001293 | Pride

Transcriptomic analysis of investigation of the Type VII protein secretion system in Staphylococcus aureus

Project description:RNA-Seq on 8 samples with cells harvested at mid log phase to investigate T7SS system in Staphylococcus aureus.These data are part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

2015-05-26 | E-ERAD-362 | biostudies-arrayexpress

Temporal and ligand effects on phagosome maturation

Project description:Systems biology analysis of temporally-resolved phagosome proteomes following uptake via key phagocytic receptors Macrophages operate at the forefront of innate immunity, and their discrimination of pathogenic versus “self” particles is critical for a number of responses including efficient pathogen killing, antigen presentation and cytokine induction. In order to efficiently phagocytose and destroy the particles, macrophages express an array of receptors to sense and internalise prey particles. In this manuscript, particles conjugated to seven ligands representing pathogen-associated molecular patterns, immune opsonins or apoptotic cell markers were inoculated to murine bone marrow-derived macrophages (BMDMs) and proteomes of isolated phagosomes were accurately quantified among conditions and across a timecourse. While we identified a clear functional differentiation over the three timepoints, only subtle differences were detected between certain ligand-phagosomes, suggesting that triggering of receptors through a single ligand has only mild effects on phagosome proteome and function. This data shows for the first time a systematic time-course analysis of BMDM phagosomes and how phagosome fate is regulated by the receptors triggered for phagocytosis.

2015-09-10 | PXD000772 | Pride

SWATH-LC/MS/MS of the proteomic response in Campylobacter jejuni 81-176 to sublethal concentrations of seven different bile acids

Project description:To characterize the adaptation processes of C. jejuni to sublethal concentrations of bile acids, that are a crucial component of the intestinal antimicrobial defense, including cholic- , chenodeoxycholic-, taurocholic-, glycocholic-, deoxycholic-, lithocholic-, and ursodeoxycholic acid, we used proteome profiling by label-free mass spectrometry (SWATH-MS). The most toxic bile acids, deoxycholic- and chenodeoxycholic acid induced the most significant changes in protein expression. In detail we found a significant down-regulation of in principle all basic biosynthetic pathways and a general decrease of the transcription machinery. Concurrently, an induction of factors involved in detoxification of reactive oxygen species, protein folding, and bile acid exporting efflux pumps was detected. The metabolism was optimized in such a way that the more energy-efficient aerobic respiration pathway was increased, while the energy-inefficient anaerobic branches of the electron transport chain were down-regulated. Uptake of amino acids in order to catabolize them was also increased. These results show that C. jejuni has a well-built, differentiated system of adaptation to bile acids stress. The findings of this study will enhance the understanding of the biology on the interaction of C. jejuni with the human intestine, and may provide clues to future medical treatment and prevention of C. jejuni infections.

2018-10-01 | PXD009088 | Pride

The ESX-4 type VII secretion system in required for efficient heme utilization by Mycobacterium tuberculosis

Project description:In this study our primary objective was to identify unknown components that are required of Mtb Hm acquisition. Herein, we show that the ancestral ESX-4 type VII secretion system (T7SS) which was thought to be inactive in Mtb is required for efficient Hm utilization. We also identified that the culture filtrate proteins Rv0125 and Rv1085c and the alternative sigma factor SigM are necessary of Hm utilization. Finally, we present the first direct evidence that some mycobacterial PPE proteins are pore forming membrane proteins.

2023-01-31 | PXD036081 | Pride

Foxp3 positive and negative cell comparison

Project description:Regulatory T cells have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and in addition the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. ATP was secreted by both T effector and regulatory T cells and was reduced by mitochondrial respiration inhibitors. Thus Foxp3 imparts a selective advantage in ATP generation capacity to the cell and may exploit this as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a comparative quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing T cells and Foxp3 positive iTreg and Foxp3 negative activated CD4 T cells in addition to human peripheral blood natural Treg. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 drives a significant up regulation of several members of the mitochondrial electron transport chain.

2017-02-15 | PXD001789 | Pride

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2015-09-16 | PXD002127 | Pride