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The cytotoxic Staphylococcus aureus PSM?3 reveals a cross-? amyloid-like fibril.

ABSTRACT: Amyloids are ordered protein aggregates, found in all kingdoms of life, and are involved in aggregation diseases as well as in physiological activities. In microbes, functional amyloids are often key virulence determinants, yet the structural basis for their activity remains elusive. We determined the fibril structure and function of the highly toxic, 22-residue phenol-soluble modulin ?3 (PSM?3) peptide secreted by Staphylococcus aureus PSM?3 formed elongated fibrils that shared the morphological and tinctorial characteristics of canonical cross-? eukaryotic amyloids. However, the crystal structure of full-length PSM?3, solved de novo at 1.45 angstrom resolution, revealed a distinctive "cross-?" amyloid-like architecture, in which amphipathic ? helices stacked perpendicular to the fibril axis into tight self-associating sheets. The cross-? fibrillation of PSM?3 facilitated cytotoxicity, suggesting that this assembly mode underlies function in S. aureus.

SUBMITTER: Tayeb-Fligelman E

PROVIDER: S-EPMC6372758 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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The cytotoxic <i>Staphylococcus aureus</i> PSMα3 reveals a cross-α amyloid-like fibril.

Tayeb-Fligelman Einav E Tabachnikov Orly O Moshe Asher A Goldshmidt-Tran Orit O Sawaya Michael R MR Coquelle Nicolas N Colletier Jacques-Philippe JP Landau Meytal M

Science (New York, N.Y.) 20170201 6327

Amyloids are ordered protein aggregates, found in all kingdoms of life, and are involved in aggregation diseases as well as in physiological activities. In microbes, functional amyloids are often key virulence determinants, yet the structural basis for their activity remains elusive. We determined the fibril structure and function of the highly toxic, 22-residue phenol-soluble modulin α3 (PSMα3) peptide secreted by <i>Staphylococcus aureus</i> PSMα3 formed elongated fibrils that shared the morph ...[more]

PMID: 28232575

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Project description:Staphylococcus aureus (Sa), as one of the major human pathogens, has very effective strategies to subvert the human immune system. Virulence of the emerging community-associated methicillin-resistant Sa (CA-MRSA) depends on the secretion of phenol-soluble modulin (PSM) peptide toxins e.g., by binding to and modulation of innate immune cells. Previously, by using mouse bone marrow-derived dendritic cells we demonstrated that PSMs in combination with various Toll-like receptor (TLR) ligands induce a tolerogenic DC phenotype (tDC) characterized by the production of IL-10 and impaired secretion of pro-inflammatory cytokines. Consequently, PSM-induced tDCs favored priming of CD4+CD25+FoxP3+ Tregs with suppressor function while impairing the Th1 response. However, the relevance of these findings for the human system remained elusive. Here, we analyzed the impact of PSM?3 on the maturation, cytokine production, antigen uptake, and T cell stimulatory capacity of human monocyte-derived DCs (moDCs) treated simultaneously with either LPS (TLR4 ligand) or Sa cell lysate (TLR2 ligand). Herein, we demonstrate that PSMs indeed modulate human moDCs upon treatment with TLR2/4 ligands via multiple mechanisms, such as transient pore formation, impaired DC maturation, inhibited pro- and anti-inflammatory cytokine secretion, as well as reduced antigen uptake. As a result, the adaptive immune response was altered shown by an increased differentiation of naïve and even CD4+ T cells from patients with Th1/Th17-induced diseases (spondyloarthritis and rheumatoid arthritis) into CD4+CD127-CD25hiCD45RA-FoxP3hi regulatory T cells (Tregs) with suppressor function. This Treg induction was mediated most predominantly by direct DC-T-cell interaction. Thus, PSMs from highly virulent Sa strains affect DC functions not only in the mouse, but also in the human system, thereby modulating the adaptive immune response and probably increasing the tolerance toward the bacteria. Moreover, PSM?3 might be a novel peptide for tolerogenic DC induction that may be used for DC vaccination strategies.

Project description:Phenol-soluble modulins (PSMs) are amphipathic peptides that are produced by staphylococci and play important roles in Staphylococcus aureus biofilm formation and dissemination. Although the multiple functions of PSMs have been recognized, the regulatory mechanisms controlling the expression of psm operons remain largely unknown. In this study, we identified MgrA in a DNA pulldown assay and further demonstrated, by electrophoretic mobility shift assays and DNase I footprinting assays, that MgrA could bind specifically to the promoter regions of psm operons. We then constructed an isogenic mgrA deletion strain and compared biofilm formation and detachment in the wild-type and isogenic mgrA deletion strains. Our results indicated that biofilm formation and detachment were significantly increased in the mgrA mutant strain. Real-time quantitative reverse transcription-PCR data indicated that MgrA repressed the transcription of psm operons in cultures and biofilms, suggesting that MgrA is a negative regulator of psm expression. Furthermore, we analyzed biofilm formation by the psm mutant strains, and we found that PSMs promoted biofilm structuring and development in the mgrA mutant strain. These findings reveal that MgrA negatively regulates biofilm formation and detachment by repressing the expression of psm operons through direct binding to the psm promoter regions.IMPORTANCEStaphylococcus aureus is a human and animal pathogen that can cause biofilm-associated infections. PSMs have multiple functions in biofilm development and virulence in staphylococcal pathogenesis. This study has revealed that MgrA can negatively regulate psm expression by binding directly to the promoter regions of psm operons. Furthermore, our results show that MgrA can modulate biofilm structuring and development by repressing the production of PSMs in S. aureus Our findings provide novel insights into the regulatory mechanisms of S. aureus psm gene expression, biofilm development, and pathogenesis.

Dataset Information

The cytotoxic Staphylococcus aureus PSM?3 reveals a cross-? amyloid-like fibril.

Publications

The cytotoxic <i>Staphylococcus aureus</i> PSMα3 reveals a cross-α amyloid-like fibril.

Similar Datasets

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