Activation of Akt/Protein Kinase B in Epithelial Cells by theSalmonella typhimurium Effector SigD

Steele‐Mortimer, Olivia; Knodler, Leigh A.; Marcus, Sandra L.; Scheid, Michael P.; Goh, Benjamin; Pfeifer, Cheryl G.; Duronio, Vincent; Finlay, B. Brett

doi:10.1074/jbc.m008187200

Cited by 179 publications

(264 citation statements)

References 45 publications

(17 reference statements)

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“…SopB is an inositol phosphate phosphatase that plays an important role in cell invasion and enteropathogenesis and is involved in protecting epithelial cells from apoptosis through Akt activation [16–19,44]. Likewise, SopB promotes the accumulation of PI(3,4)P2/PI(3,4,5)P3 at the cell membrane, which leads to Akt recruitment and activation by PDK1 and mTORC2.…”

Section: Discussionmentioning

confidence: 99%

“…SopE/SopE2 and the inositide phosphate phosphatase SopB are some of the effector proteins responsible for the induction of macropinocytosis. SopB is also involved in host cell survival through activation of the Akt signaling pathway [16,18,19]. Additional functions have recently been described for SPI-1, including activation of the host innate immune system and induction of cell death [20,21].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…S. enterica serovar Typhimurium SL1344 (26) and the sopB deletion mutant (⌬sopB mutant) (30,54) were grown overnight with shaking (200 rpm) in Luria-Bertani (LB) broth supplemented with 50 g/ml streptomycin at 37°C for 18 h.…”

Section: Methodsmentioning

confidence: 99%

“…One SPI1 translocated effector protein, SopB, has previously been shown to be required for the activation of Akt in infected epithelial cells (54). The serine/threonine kinase Akt is expressed in 3 distinctly coded isoforms, namely Akt1, Akt2, and Akt3 (48).…”

mentioning

confidence: 99%

Protective Role of Akt2 in Salmonella enterica Serovar Typhimurium-Induced Gastroenterocolitis

Kum

2011

Infect Immun

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The Salmonella effector protein SopB has previously been shown to induce activation of Akt and protect epithelial cells from apoptosis in vitro. To characterize the role of Akt2 in host defense against Salmonella enterica serovar Typhimurium infection, wild-type (WT) mice and mice lacking Akt2 (Akt2 knockout [KO] mice) were infected using a Salmonella acute gastroenteritis model. Infected Akt2 KO mice showed a more pronounced morbidity and mortality associated with higher bacterial loads in the intestines and elevated levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), and MCP-1, in the colons at 1 day postinfection compared to those shown in WT mice. Histopathological assessment and immunohistochemical analysis of cecal sections at 1 day postinfection revealed more severe inflammation and higher levels of neutrophil infiltration in the ceca of Akt2 KO mice. Flow cytometry analysis further confirmed an increase in the recruitment of Gr-1 ؉ CD11b ؉ neutrophils and F4/80 ؉ CD11b ؉ macrophages in the intestines of infected Akt2 KO mice. Additionally, enhanced levels of annexin V ؉ and terminal transferase dUTP nick end labeling-positive (TUNEL ؉ ) apoptotic cells in the intestines of infected Akt2 KO mice were also observed, indicating that Akt2 plays an essential role in protection against apoptosis. Finally, the differences in bacterial loads and cecal inflammation in WT and Akt2 KO mice infected with WT Salmonella were abolished when these mice were infected with the sopB deletion mutant, indicating that SopB may play a role in protecting the mice from Salmonella infection through the activation of Akt2. These data demonstrate a definitive phenotypic abnormality in the innate response in mice lacking Akt2, underscoring the important protective role of Akt2 in Salmonella infection.

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“…3A). AvrA and SopB, whose antiapoptotic activities are already known [25,26], could contribute to the delay in cell death that is observed during infections of epithelial cells. This is probably beneficial for the pathogen because it allows the establishment of a stable intracellular niche and contributes to avoid adaptive immunity.…”

Section: Stea Decreases Epithelial Cell Deathmentioning

confidence: 99%

Global impact of Salmonella type III secretion effector SteA on host cells

Cardenal‐Muñoz

Gutiérrez

Ramos‐Morales

2014

Biochemical and Biophysical Research Communications

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Salmonella enterica is a Gram-negative bacterium that causes gastroenteritis, bacteremia and typhoid fever in several animal species including humans. Its virulence is greatly dependent on two type III secretion systems, encoded in pathogenicity islands 1 and 2. These systems translocate proteins called effectors into eukaryotic host cell. Effectors interfere with host signal transduction pathways to allow the internalization of pathogens and their survival and proliferation inside vacuoles. SteA is one of the few Salmonella effectors that are substrates of both type III secretion systems. Here, we used gene arrays and bioinformatics analysis to study the genetic response of human epithelial cells to SteA. We found that constitutive synthesis of SteA in HeLa cells leads to induction of genes related to extracellular matrix organization and regulation of cell proliferation and serine/threonine kinase signaling pathways. SteA also causes repression of genes related to immune processes and regulation of purine nucleotide synthesis and pathway-restricted SMAD protein phosphorylation. In addition, a cell biology approach revealed that epithelial cells expressing steA show altered cell morphology, and decreased cytotoxicity, cell-cell adhesion and migration.

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Activation of Akt/Protein Kinase B in Epithelial Cells by theSalmonella typhimurium Effector SigD

Cited by 179 publications

References 45 publications

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

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

Protective Role of Akt2 in Salmonella enterica Serovar Typhimurium-Induced Gastroenterocolitis

Global impact of Salmonella type III secretion effector SteA on host cells

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