Salmonella activation of STAT3 signaling by SarA effector promotes intracellular replication and production of IL-10
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ABSTRACT:
PROVIDER: PRJNA412406 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6108710.fastq.gz | Fastqsanger.gz | |||
| SRR6108711.fastq.gz | Fastqsanger.gz | |||
| SRR6108712.fastq.gz | Fastqsanger.gz | |||
| SRR6108713.fastq.gz | Fastqsanger.gz | |||
| SRR6108714.fastq.gz | Fastqsanger.gz |
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Project description:Salmonella enterica is an important foodborne pathogen that utilizes secreted effector proteins to manipulate host pathways to facilitate survival and dissemination. Different S. enterica serovars cause disease syndromes ranging from self-limited gastroenteritis to typhoid fever and vary in their repertoire of effectors. We leveraged this natural diversity to identify stm2585, here designated sarA (Salmonella anti-inflammatory response activator), as a Salmonella effector secreted primary by the SPI-2 type III secretion system. SarA is necessary and sufficient to induce STAT3 phosphorylation and IL-10 production, contributing to intracellular replication in vitro and bacterial load at systemic sites in mice. These results demonstrate that Salmonella has evolved effector mechanisms for regulating a host anti-inflammatory signaling pathway important in infection, autoimmunity, and cancer.
2018-06-01 | GSE104354 | GEO
Project description:Salmonella enterica is an important foodborne pathogen that uses secreted effector proteins to manipulate host pathways to facilitate survival and dissemination. Different S. enterica serovars cause disease syndromes ranging from gastroenteritis to typhoid fever and vary in their effector repertoire. We leveraged this natural diversity to identify stm2585, here designated sarA (Salmonella anti-inflammatory response activator), as a Salmonella effector that induces production of the anti-inflammatory cytokine IL-10. RNA-seq of cells infected with either ?sarA or wild-type S. Typhimurium revealed that SarA activates STAT3 transcriptional targets. Consistent with this, SarA is necessary and sufficient for STAT3 phosphorylation, STAT3 inhibition blocks IL-10 production, and SarA and STAT3 interact by co-immunoprecipitation. These effects of SarA contribute to intracellular replication in vitro and bacterial load at systemic sites in mice. Our results demonstrate the power of using comparative genomics for identifying effectors and that Salmonella has evolved mechanisms for activating an important anti-inflammatory pathway.
| S-EPMC6314477 | biostudies-literature
Project description:The staphylococcal accessory regulator A (sarA) impacts the extracellular accumulation of Staphylococcus aureus virulence factors at the level of intracellular production and extracellular protease-mediated degradation. To assess the relative impact of these two functions, we previously used a proteomics approach that measures protein abundance as a function of all proteoforms to demonstrate that mutation of sarA results in increased levels of extracellular proteases and assess the impact of this on the accumulation of S. aureus exoproteins1. While this approach confirmed that protease-mediated degradation has a significant impact on the S. aureus exoproteome, it was potentially limited in that it did not take into account the possibility that large, stable proteolytic products from a given protein could result in false negatives when quantified by total proteoforms. Here, we present an expanded proteomics approach that utilizes a dual quantitative method for measuring abundance at both the total proteoform and full-length exoprotein levels. Specifically, proteins present in conditioned medium from overnight, stationary phase cultures of the USA300 strain LAC, an isogenic sarA mutant, and a sarA mutant unable to produce any of the known extracellular proteases (sarA/protease) were resolved using one-dimensional gel electrophoresis. Using methods that focus on total proteoforms vs. methods that focus specifically on full-length proteins, quantitative proteomic comparisons of sarA vs sarA/protease mutants identified proteins that were degraded in a protease dependent manner owing to mutation of sarA, while comparisons of a sarA/protease mutant vs the LAC parent strain identified proteins in which abundance was altered in a sarA mutant in a protease-independent manner. Furthermore, the proteins uniquely identified by the full-length data analysis approach eliminated false negatives observed in the total proteoform analysis. This approach provided for a more comprehensive and robust analysis of the impact of mutating sarA and protease-mediated degradation on the S. aureus exoproteome.
2018-11-21 | PXD009614 | Pride
Project description:ChIP seq for SarA in S. aureus HG003 wild type and HG003 DsarA
2021-05-11 | GSE174162 | GEO
Project description:Chronically infecting pathogens avoid clearance by the innate immune system by promoting premature transition from an initial pro-inflammatory response towards an anti-inflammatory tissue-repair response. STAT3, a central regulator of inflammation, controls this transition and thus is targeted by numerous chronic pathogens. Here we show that BepD, an effector of the chronic bacterial pathogen Bartonella henselae targeted to infected host cells, establishes an exceptional pathway for canonical STAT3 activation, thereby impairing secretion of pro-inflammatory TNF-α and stimulating secretion of anti-inflammatory IL-10. Tyrosine phosphorylation of EPIYA-related motifs in BepD facilitates STAT3 binding and activation via c-Abl-dependent phosphorylation of Y705. The tyrosine-phosphorylated scaffold of BepD thus represents a signaling hub for intrinsic STAT3 activation that is independent from canonical STAT3 activation via transmembrane receptor-associated Janus kinases. We anticipate that our findings on a molecular shortcut to STAT3 activation will inspire new treatment options for chronic infections and inflammatory diseases.
2020-02-12 | PXD017119 | Pride
Project description:<p><em>Salmonella Typhimurium</em> establishes systemic infection by replicating in host macrophages. Here we show that macrophages infected with <em>S. Typhimurium</em> exhibit upregulated glycolysis and decreased serine synthesis, leading to accumulation of glycolytic intermediates. The effects on serine synthesis are mediated by bacterial protein SopE2, a type III secretion system (T3SS) effector encoded in pathogenicity island SPI-1. The changes in host metabolism promote intracellular replication of <em>S. Typhimurium</em> via two mechanisms: decreased glucose levels lead to upregulated bacterial uptake of 2- and 3-phosphoglycerate and phosphoenolpyruvate (carbon sources), while increased pyruvate and lactate levels induce upregulation of another pathogenicity island, SPI-2, known to encode virulence factors. Pharmacological or genetic inhibition of host glycolysis, activation of host serine synthesis, or deletion of either the bacterial transport or signal sensor systems for those host glycolytic intermediates impairs <em>S. Typhimurium</em> replication or virulence.</p>
2024-05-22 | MTBLS2347 | MetaboLights
Project description:This study is to identify downstream genes regulated by STAT3 in response cytosolic acidification. Dysregulated intracellular pH is emerging as a hallmark of cancer. In spite of their acidic environment, cancer cells maintain alkaline intracellular pH (≥7.4) that promotes cancer progression by inhibiting apoptosis and increasing glycolysis, cell growth, migration and invasion. Here, we identify signal transducer and activator of transcription 3 (STAT3) as a key player in the maintenance of alkaline cytosolic pH. STAT3 associates with the vacuolar H+-ATPase on lysosomal membranes in a coiled coil domain-dependent manner and increases its activity in living cells and in vitro. Accordingly, STAT3 depletion disrupts intracellular proton equilibrium by decreasing and increasing cytosolic and lysosomal pH, respectively. This dysregulation can be reverted by reconstitution with wild type STAT3 as well as STAT3 mutants unable to activate target genes (Tyr-705-Phe and DNA binding mutant) or to regulate mitochondrial respiration (Ser-727-Ala). Upon cytosolic acidification, phospho-Tyr-705-STAT3 is rapidly dephosphorylated, transcriptionally inactivated and further recruited to lysosomal membranes to reestablish intracellular proton equilibrium and to enhance cell survival. These data reveal STAT3 as a regulator of intracellular pH, and vice versa intracellular pH as a regulator of STAT3 localization and activity.
2018-01-03 | GSE108495 | GEO
Project description:Activated myofibroblasts play an essential role in tissue fibrogenesis by producing extracellular matrixes (ECM). ECMs replace normal functioning tissue, reducing tissue plasticity and impairing functions of the organ. Recent studies suggested that pericytes are a major source of myofibroblast precursors. We previously showed that Smad Anchor for Receptor Activation (SARA) prevents cellular phenotypic transdifferentiation toward mesenchymal cells, and depletion of SARA induces transdifferentiation of epithelial cells to fibroblast-like phenotype. Here, we generated a transgenic mice that overexpress SARA specifically pericytes by using PDGFRβ-Cre (SARATg, PDGFRβ-Cre). When subjected to either subcutaneous injection of bleomycin or intraperitoneal administration of aristolochic acid, which induces skin and kidney fibrosis, respectively, SARATg, PDGFRβ-Cre mice developed significantly less fibrosis compared to SARAWT, PDGFRβ-Cre mice. To decipher molecular signature and pericyte trajectory under fibrotic conditions and effects of SARA overexpression, we isolated PDGFR+ cells from skin or kidney of SARATg or WT, PDGFRβ-Cre, Z/EG mice with or without fibrotic stimuli and performed scRNAseq analyses. In both skin and kidney sample sets, we found pericytes and immune cell populations are the major cell components among the PDGFR+ GFP+ cells. We found that pericyte populations are divided into canonical and non-canonical sub-populations and the latter has assumed myofibroblast characteristics. Trajectory mapping revealed a single path from canonical to non-canonical pericyte sub-populations and SARA overexpression truncated the trajectory. These results suggest that SARA prevents pericyte transdifferentiation into myofibroblasts under fibrotic condition, and therefore anti-fibrotic.
2022-11-23 | GSE211810 | GEO
Project description:Bacteria masterfully co-opt and subvert host signal transduction. As a paradigmatic example, Salmonella uses two type-3 secretion systems to inject effector proteins that facilitate Salmonella entry, establishment of an intracellular niche, and modulation of immune responses. We previously demonstrated that the Salmonella anti-inflammatory response activator SarA (Stm2585, GogC, PagJ, SteE) activates the host transcription factor STAT3 to drive expression of immunomodulatory STAT3-targets. Here, we demonstrate-by sequence, function, and biochemical measurement-that SarA mimics the cytoplasmic domain of glycoprotein 130 (gp130, IL6ST). SarA is phosphorylated at a YxxQ motif, facilitating binding to STAT3 with greater affinity than gp130. Departing from canonical gp130 signaling, SarA function is JAK-independent but requires GSK-3, a key regulator of metabolism and development. Our results reveal that SarA undergoes host phosphorylation to recruit a STAT3-activating complex, circumventing cytokine receptor activation. Effector mimicry of gp130 suggests GSK-3 can regulate normal cytokine signaling, potentially enabling metabolic and immune crosstalk.
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