c-KIT signaling is targeted by pathogenic Yersiniato suppress the host immune response

Micheva-Viteva, Sofiya; Shou, Yulin; Nowak‐Lovato, Kristy; Rector, Kirk D.; Hong-Geller, Elizabeth

doi:10.1186/1471-2180-13-249

Cited by 10 publications

(13 citation statements)

References 63 publications

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“…In a previous study, we had demonstrated that pathogenic Yersinia species employ the virulence plasmid pCD1 to inhibit EGR1 and pro-inflammatory cytokine gene expression. [24] KD strains of Y . pseudotuberculosis and Y .…”

Section: Resultsmentioning

confidence: 99%

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Functional and Structural Analysis of a Highly-Expressed Yersinia pestis Small RNA following Infection of Cultured Macrophages

Hennelly

Stubben

et al. 2016

PLoS ONE

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Non-coding small RNAs (sRNAs) are found in practically all bacterial genomes and play important roles in regulating gene expression to impact bacterial metabolism, growth, and virulence. We performed transcriptomics analysis to identify sRNAs that are differentially expressed in Yersinia pestis that invaded the human macrophage cell line THP-1, compared to pathogens that remained extracellular in the presence of host. Using ultra high-throughput sequencing, we identified 37 novel and 143 previously known sRNAs in Y. pestis. In particular, the sRNA Ysr170 was highly expressed in intracellular Yersinia and exhibited a log2 fold change ~3.6 higher levels compared to extracellular bacteria. We found that knock-down of Ysr170 expression attenuated infection efficiency in cell culture and growth rate in response to different stressors. In addition, we applied selective 2’-hydroxyl acylation analyzed by primer extension (SHAPE) analysis to determine the secondary structure of Ysr170 and observed structural changes resulting from interactions with the aminoglycoside antibiotic gentamycin and the RNA chaperone Hfq. Interestingly, gentamicin stabilized helix 4 of Ysr170, which structurally resembles the native gentamicin 16S ribosomal binding site. Finally, we modeled the tertiary structure of Ysr170 binding to gentamycin using RNA motif modeling. Integration of these experimental and structural methods can provide further insight into the design of small molecules that can inhibit function of sRNAs required for pathogen virulence.

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Section: Resultsmentioning

confidence: 99%

“…pestis . (Fig 4D) Given that pro-inflammatory cytokine and EGR1 expression in macrophages are suppressed by pCD1 [25, 27], we tested whether the KD strain of Y . pestis cured of pCD1 can alter IL-8/EGR1 expression levels, in addition to TNF-α production.…”

Section: Resultsmentioning

confidence: 99%

Functional and Structural Analysis of a Highly-Expressed Yersinia pestis Small RNA following Infection of Cultured Macrophages

Hennelly

Stubben

et al. 2016

PLoS ONE

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“…KIT can activate several signaling pathways including activation of Akt/PI3K, STAT1/3/5, and PLCG1. PI3K pathway is required for successful infection of intracellular bacteria (Jiwani et al, ; Kuijl et al, ; Micheva‐Viteva, Shou, Nowak‐Lovato, Rector, & Hong‐Geller, ). In Plasmodium HGF/MET signaling protects infected host cells via activation of PI3K pathway (Leiriao et al, ).…”

Section: Discussionmentioning

confidence: 99%

Modulation of host cell SUMOylation facilitates efficient development of Plasmodium berghei and Toxoplasma gondii

Maruthi

Singh

Reddy

et al. 2017

Cellular Microbiology

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SUMOylation is a reversible post translational modification of proteins that regulates protein stabilization, nucleocytoplasmic transport, and protein-protein interactions. Several viruses and bacteria modulate host SUMOylation machinery for efficient infection. Plasmodium sporozoites are infective forms of malaria parasite that invade mammalian hepatocytes and transforms into exoerythrocytic forms (EEFs). Here, we show that during EEF development, the distribution of SUMOylated proteins in host cell nuclei was significantly reduced and expression of the SUMOylation enzymes was downregulated. Plasmodium EEFs destabilized the host cytoplasmic protein SMAD4 by inhibiting its SUMOylation. SUMO1 overexpression was detrimental to EEF growth, and insufficiency of the only conjugating enzyme Ubc9/E2 promoted EEF growth. The expression of genes involved in suppression of host cell defense pathways during infection was reversed during SUMO1 overexpression, as revealed by transcriptomic analysis. The inhibition of host cell SUMOylation was also observed during Toxoplasma infection. We provide a hitherto unknown mechanism of regulating host gene expression by Apicomplexan parasites through altering host SUMOylation.

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“…Pharmacological inhibition of c-Kit results in increased activation of NF-κB in HEK293 cells and secretion of TNFα in dendritic cells and the THP-1 monocytic cell line in response to bacterial infection (Micheva-Viteva et al, 2013). Lower expressions of SCF and c-Kit were also associated with increased NF-κB signaling and oxidative stress in gastric smooth muscle (Jin et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

c-Kit modifies the inflammatory status of smooth muscle cells

Song

Martinez

Zigmond

et al. 2017

PeerJ

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Backgroundc-Kit is a receptor tyrosine kinase present in multiple cell types, including vascular smooth muscle cells (SMC). However, little is known about how c-Kit influences SMC biology and vascular pathogenesis.MethodsHigh-throughput microarray assays and in silico pathway analysis were used to identify differentially expressed genes between primary c-Kit deficient (KitW/W–v) and control (Kit+/+) SMC. Quantitative real-time RT-PCR and functional assays further confirmed the differences in gene expression and pro-inflammatory pathway regulation between both SMC populations.ResultsThe microarray analysis revealed elevated NF-κB gene expression secondary to the loss of c-Kit that affects both the canonical and alternative NF-κB pathways. Upon stimulation with an oxidized phospholipid as pro-inflammatory agent, c-Kit deficient SMC displayed enhanced NF-κB transcriptional activity, higher phosphorylated/total p65 ratio, and increased protein expression of NF-κB regulated pro-inflammatory mediators with respect to cells from control mice. The pro-inflammatory phenotype of mutant cells was ameliorated after restoring c-Kit activity using lentiviral transduction. Functional assays further demonstrated that c-Kit suppresses NF-κB activity in SMC in a TGFβ-activated kinase 1 (TAK1) and Nemo-like kinase (NLK) dependent manner.DiscussionOur study suggests a novel mechanism by which c-Kit suppresses NF-κB regulated pathways in SMC to prevent their pro-inflammatory transformation.

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c-KIT signaling is targeted by pathogenic Yersiniato suppress the host immune response

Cited by 10 publications

References 63 publications

Functional and Structural Analysis of a Highly-Expressed Yersinia pestis Small RNA following Infection of Cultured Macrophages

Functional and Structural Analysis of a Highly-Expressed Yersinia pestis Small RNA following Infection of Cultured Macrophages

Modulation of host cell SUMOylation facilitates efficient development of Plasmodium berghei and Toxoplasma gondii

c-Kit modifies the inflammatory status of smooth muscle cells

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