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

Abstract

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.

<p>Molecular Mechanisms of <em>Salmonella</em> Effector Proteins: A Comprehensive Review</p>

“…39 Phosphatase activity can reduce phosphatidylinositol biphosphate PI (3,4) and induce Akt (Protein kinase B that regulates cell survival) to ensure the best bacterial growth inside the cell and inhibit apoptosis. [40][41][42] The reduction of the phosphatidylinositol biphosphate leads to a decrease in negative charge on the surface of Salmonella-containing vacuole (SCV), resulting in the prevention of lysosomal enzyme fusion. 43 After the invasion and lipid activity of SopB, RhoH, RhoD, RhoB, and RhoJ recurred within the location of Salmonella invasion.…”

Beyond the antibody: B cells as a target for bacterial infection

“…Furthermore, in response to Salmonella infection, spleen mouse B cells are able to produce TNF‐α and IL‐6 as macrophages do, but they do not secrete IL‐1β in a process dependent on the inositide phosphate phosphatase SopB . By translocation of SopB to the cytosol of mouse spleen B cells, Salmonella activates the PI3K‐Akt‐YAP pathway to down‐regulate NLRC4 expression and prevent IL‐1β secretion . YAP is a transcriptional coactivator necessary for efficient Nlrc4 transcription.…”

“…31 By translocation of SopB to the cytosol of mouse spleen B cells, Salmonella activates the PI3K-Akt-YAP pathway to down-regulate NLRC4 expression and prevent IL-1 secretion. 32,33 YAP is a transcriptional coactivator necessary for efficient Nlrc4 transcription. When phosphorylated by Akt, YAP is sequestered in the cytoplasm, so by activating Akt, Salmonella regulates IL-1 secretion.…”

“…When infected with a ΔsopB strain or when infected in the presence of PI3K-Akt inhibitors, the production of IL-1 by B cells is restored. 33 Remarkably, Salmonella not only blocks IL-1 secretion by mouse spleen B cells but also promotes IL-10 production, a process that has been reported to prevent Salmonella control by promoting a tolerogenic immune response that prevents bacterial clearance and supports systemic dissemination. 2,33 Recently, Jaslow established a mechanism used by Salmonella Thyphimurium to promote IL-10 production in infected human LCL.…”

“…When phosphorylated by Akt, YAP is sequestered in the cytoplasm, so by activating Akt, Salmonella regulates IL‐1β secretion. When infected with a ΔsopB strain or when infected in the presence of PI3K‐Akt inhibitors, the production of IL‐1β by B cells is restored . Remarkably, Salmonella not only blocks IL‐1β secretion by mouse spleen B cells but also promotes IL‐10 production, a process that has been reported to prevent Salmonella control by promoting a tolerogenic immune response that prevents bacterial clearance and supports systemic dissemination .…”