Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1

Kuijl, Coenraad; Savage, Nigel D. L.; Marsman, Marije; Tuin, Adriaan W.; Janssen, Lennert; Egan, David A.; Ketema, Mirjam; Nieuwendijk, Rian van den; Eeden, Susan J. F. van den; Geluk, Annemieke; Poot, Alex J.; Marel, Gijs van der; Beijersbergen, Roderick L.; Overkleeft, Hermen S.; Ottenhoff, Tom H. M.; Neefjes, Jacques

doi:10.1038/nature06345

Cited by 286 publications

(319 citation statements)

References 48 publications

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“…Up to half of host phosphorylation events during Salmonella infection have been directly linked to SopB, and this modulation of processes via phosphorylation is key to promote host cell and Salmonella survival [46–48]. Our results fully demonstrated that in B cells, Salmonella SopB promotes YAP phosphorylation through Akt and plays a role in this signal transduction pathway that allows inhibition of the NLRC4 inflammasome.…”

Section: Discussionsupporting

confidence: 60%

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: Discussionsupporting

confidence: 60%

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

et al. 2018

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“…The ability of Mtb to keep its host cell alive should ultimately favor bacterial survival and replication inside the host. Although the exact mechanism by which mPTPB activates Akt awaits further investigation, it is noteworthy that Akt has also been shown to be important for intracellular growth of unrelated pathogens such as Salmonella typhimurium and Mtb (16). Taken together, the results from the above experiments indicate that mPTPB functions to overcome host defense mechanisms during infection by attenuating the bactericidal immune responses and promoting macrophage survival.…”

Section: Resultsmentioning

confidence: 53%

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Zhou¹,

He²,

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

209

205

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Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.combinatorial chemistry | pathogen-host interaction | phosphatase inhibitor | signaling mechanism

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“…WT-AKT and DN-AKT were kind gifts from Dr. Jacques Neefjes (Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands). 42 WT-GSK-3β (HA-GSK-3β WT pcDNA3) and CA-GSK-3β (HA-GSK-3β S9A pcDNA3) were gift from Dr Jim Woodgett (Addgene plasmid # 14753 and Addgene Plasmid 14754, respectively). 43,44 WT-FOXO-1 (GFP-FOXO-1) and CA-FOXO-1 (FOXO-1-ADA-GFP) were gift from Dr. Domenico Accili (Addgene plasmid # 17551 and Addgene Plasmid 35640, respectively).…”

Section: Methodsmentioning

confidence: 99%

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

et al. 2016

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In order to establish infection, intra-macrophage parasite Leishmania donovani needs to inhibit host defense parameters like inflammatory cytokine production and apoptosis. In the present study, we demonstrate that the parasite achieves both by exploiting a single host regulator AKT for modulating its downstream transcription factors, β-catenin and FOXO-1. L. donovaniinfected RAW264.7 and bone marrow-derived macrophages (BMDM) treated with AKT inhibitor or dominant negative AKT constructs showed decreased anti-inflammatory cytokine production and increased host cell apoptosis resulting in reduced parasite survival. Infection-induced activated AKT triggered phosphorylation-mediated deactivation of its downstream target, GSK-3β. Inactivated GSK-3β, in turn, could no longer sequester cytosolic β-catenin, an anti-apoptotic transcriptional regulator, as evidenced from its nuclear translocation during infection. Constitutively active GSK-3β-transfected L. donovani-infected cells mimicked the effects of AKT inhibition and siRNA-mediated silencing of β-catenin led to disruption of mitochondrial potential along with increased caspase-3 activity and IL-12 production leading to decreased parasite survival. In addition to activating antiapoptotic β-catenin, phospho-AKT inhibits activation of FOXO-1, a pro-apoptotic transcriptional regulator. Nuclear retention of FOXO-1, inhibited during infection, was reversed when infected cells were transfected with dominant negative AKT constructs. Overexpression of FOXO-1 in infected macrophages not only documented increased apoptosis but promoted enhanced TLR4 expression and NF-κB activity along with an increase in IL-1β and decrease in IL-10 secretion. In vivo administration of AKT inhibitor significantly decreased liver and spleen parasite burden and switched cytokine balance in favor of host. In contrast, GSK-3β inhibitor did not result in any significant change in infectivity parameters. Collectively our findings revealed that L. donovani triggered AKT activation to regulate GSK-3β/β-catenin/FOXO-1 axis, thus ensuring inhibition of both host cell apoptosis and immune response essential for its intra-macrophage survival.

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Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1

Cited by 286 publications

References 48 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

Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

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