Activation of Akt by the Bacterial Inositol Phosphatase, SopB, is Wortmannin Insensitive

Cooper, Kendal G.; Winfree, Seth; Malik-Kale, Preeti; Jolly, Carrie; Ireland, Robin; Knodler, Leigh A.; Steele‐Mortimer, Olivia

doi:10.1371/journal.pone.0022260

Cited by 35 publications

(32 citation statements)

References 64 publications

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“…S . Typhimurium inhibition of PCD is dependent on SopB phosphorylation and activation of the apoptosis inhibitor Akt as previously described and not through caspase-3 turnover as is the case with AIEC [47]. Therefore, it is likely that caspase-3 levels are tightly controlled in S .…”

Section: Discussionmentioning

confidence: 74%

Increased S-Nitrosylation and Proteasomal Degradation of Caspase-3 during Infection Contribute to the Persistence of Adherent Invasive Escherichia coli (AIEC) in Immune Cells

et al. 2013

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Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn’s disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients.

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Section: Discussionmentioning

confidence: 74%

Increased S-Nitrosylation and Proteasomal Degradation of Caspase-3 during Infection Contribute to the Persistence of Adherent Invasive Escherichia coli (AIEC) in Immune Cells

et al. 2013

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“…PIP3 production by PI3K leads to Akt recruitment to the plasma membrane and its activation [39]. In HeLa cells, Akt activation by SopB is class I PI3K independent, while it is class I PI3K dependent in mouse embryonic fibroblasts (MEFs) [40,41]. We evaluated if Akt activation by SopB in B cells requires class I PI3K.…”

Section: Resultsmentioning

confidence: 99%

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

et al. 2018

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B cells are a target of Salmonella infection, allowing bacteria survival without inducing pyroptosis. This event is due to downregulation of Nlrc4 expression and lack of inflammasome complex activation, which impairs the secretion of IL-1β. YAP phosphorylation is required for downregulation of Nlrc4 in B cells during Salmonella infection; however, the microorganism’s mechanisms underlying the inhibition of the NLRC4 inflammasome in B cells are not fully understood. Our findings demonstrate that the Salmonella effector SopB triggers a signaling cascade involving PI3K, PDK1 and mTORC2 that activates Akt with consequent phosphorylation of YAP. When we deleted sopB in Salmonella, infected B cells that lack Rictor, or inhibited the signaling cascade using a pharmacological approach, we were able to restore the function of the NLRC4 inflammasome in B cells and the ability to control the infection. Furthermore, B cells from infected mice exhibited activation of Akt and YAP phosphorylation, suggesting that Salmonella also triggers this pathway in vivo. In summary, our data demonstrate that the Salmonella effector inositide phosphate phosphatase SopB triggers the PI3K-Akt-YAP pathway to inhibit the NLRC4 inflammasome in B cells. This study provides further evidence that Salmonella triggers cellular mechanisms in B lymphocytes to manipulate the host environment by turning it into a survival niche to establish a successful infection.

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“…Specifically, Salmonella SopB and SopE/E2 (guanine nucleotide exchange factors) activate the Rho family guanosine triphosphatases (GTPases) and the cell division control protein 42 (Cdc42), which play a central role in the actin cytoskeleton remodeling and invasion [34]. SopB also activates phosphatidyl inositide 3 kinase (PI3 K)/Akt kinase signaling pathway, which is critical for intracellular survival [35], [36]. A recent study indicates that activation of the host cell PI3 K, Akt, and Rac-1 is required for Salmonella outer membrane protein Rck-mediated invasion [37].…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide as a Biomarker of Intracellular Salmonella Viability and Identification of the Bacteriostatic Activity of Protein Kinase A Inhibitor H-89

Genovese

Swaggerty

et al. 2013

PLoS ONE

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Salmonella enterica serovar Enteritidis is one of the most prevalent Salmonella serovars in poultry and is often associated with human salmonellosis. S. Enteritidis is known to suppress nitric oxide (NO) production in infected chicken macrophage HD11 cells, while dead S. Enteritidis stimulates a high level of NO production, suggesting a bacterial inhibitory effect on NO production. Based on these observations, the present study was conducted to evaluate whether NO production in S. Enteritidis-infected HD11 cells can be used as a biomarker to identify molecules that kill intracellular Salmonella. Since Salmonella are known to manipulate the host cell kinase network to facilitate intracellular survival, we screened a group of pharmaceutical inhibitors of various kinases to test our hypothesis. A protein kinase A inhibitor, H-89, was found to reverse the suppression of NO production in S. Enteritidis-infected HD11 cells. Production of NO in S. Enteritidis-infected HD11 cells increased significantly following treatment with H-89 at or above 20 µM. Inversely, the number of viable intracellular Salmonella decreased significantly in cells treated with H-89 at or above 30 µM. Furthermore, the growth rate of S. Enteritidis in culture was significantly inhibited by H-89 at concentrations from 20 to 100 µM. Our results demonstrate that NO-based screening using S. Enteritidis-infected HD11 cells is a viable tool to identify chemicals with anti-intracellular Salmonella activity. Using this method, we have shown H-89 has bacteriostatic activity against Salmonella, independent of host cell protein kinase A or Akt1 activity.

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Activation of Akt by the Bacterial Inositol Phosphatase, SopB, is Wortmannin Insensitive

Cited by 35 publications

References 64 publications

Increased S-Nitrosylation and Proteasomal Degradation of Caspase-3 during Infection Contribute to the Persistence of Adherent Invasive Escherichia coli (AIEC) in Immune Cells

Increased S-Nitrosylation and Proteasomal Degradation of Caspase-3 during Infection Contribute to the Persistence of Adherent Invasive Escherichia coli (AIEC) in Immune Cells

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

Nitric Oxide as a Biomarker of Intracellular Salmonella Viability and Identification of the Bacteriostatic Activity of Protein Kinase A Inhibitor H-89

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