The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt

Knodler, Leigh A.; Finlay, B. Brett; Steele‐Mortimer, Olivia

doi:10.1074/jbc.m412588200

Cited by 215 publications

(231 citation statements)

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“…Some macrophages may provide a replicative niche for Salmonella, whereas others do not. One well-documented difference between macrophages and epithelial cells is that Salmonella can induce rapid cell death in macrophages, via caspase 1, whereas in epithelial cells a prosurvival pathway is activated [34]. In addition to macrophages, Salmonella interact with a variety of highly differentiated cell types in vivo each of which may require specific adaptions by the bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…It may well be critical for SCV biogenesis but this has not been conclusively demonstrated and furthermore the in vivo substrate, or substrates, of SopB phosphatase activity remain undefined. Nonetheless, since PIs are involved either directly or indirectly in all eukaryotic cell processes, it is likely that SopB activity in the SCV membrane has additional pleiotropic effects [34]. Another T3SS1 effector that is expressed following invasion is SopD [35], a protein that may act cooperatively with SopB at least during initial formation of the phagosome [36].…”

Section: T3ss1 Effectors Mediate Early Scv Biogenesismentioning

confidence: 99%

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The Salmonella-containing vacuole—Moving with the times

Steele‐Mortimer¹

2008

Current Opinion in Microbiology

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SummarySalmonella pathogenesis is dependent on its ability to invade and replicate within host cells. Following invasion the bacteria remain within a modified phagosome known as the Salmonellacontaining vacuole (SCV), within which they will survive and replicate. Invasion and SCV biogenesis are dependent on two Type III Secretion Systems, T3SS1 & T3SS2, which are used to translocate distinct cohorts of bacterial effector proteins into the host cell. Elucidating the roles of individual effector proteins in SCV biogenesis has proven difficult but several distinct themes are now emerging and it is apparent that SCV biogenesis is an extremely dynamic process involving; extensive membrane remodeling, interactions with the endolysosomal pathway, actin rearrangements and microtubule-based movement and tubule extension.

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Section: Discussionmentioning

confidence: 99%

Section: T3ss1 Effectors Mediate Early Scv Biogenesismentioning

confidence: 99%

The Salmonella-containing vacuole—Moving with the times

Steele‐Mortimer¹

2008

Current Opinion in Microbiology

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270

277

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“…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%

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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“…A number of bacterial pathogens are able to modulate host cell survival via effects on Akt. Among these are Salmonella enterica, Shigella flexneri, and Neisseria gonorrhoeae, which inject into their host cells effector molecules that can activate Akt and thereby inhibit apoptosis during infection (Knodler et al, 2005;Edwards and Apicella, 2006;Pendaries et al, 2006). Similarly, cytotoxic necrotizing factor 1 (CNF1), a secreted toxin encoded by a number of E. coli pathogens, including some UPEC isolates, can prevent host cell apoptosis by the stimulation of Akt and subsequent NF B activation (Miraglia et al, 2007).…”

mentioning

confidence: 99%

“…UTI89 caused a marked decline in S473 phosphorylation by 90 min after infection, whereas infection with AAEC185/pSH2 did not ( Figure 1A). These results were quantified and normalized by dividing pAkt S473 levels by total Akt1 levels, as shown in the graph in Figure 1A.Some bacterial pathogens are known to actively modulate Akt signaling by secreting effector proteins into target host cells (Edwards and Apicella, 2006;Knodler et al, 2005;Pendaries et al, 2006;Ashare et al, 2007). To address this possibility with UPEC, we infected 5637 bladder cells with either live or gentamicin-killed UTI89.…”

mentioning

confidence: 99%

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

Wiles

Dhakal

Eto

et al. 2008

MBoC

102

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Uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections (UTIs), and they have the capacity to induce the death and exfoliation of target uroepithelial cells. This process can be facilitated by the pore-forming toxin ␣-hemolysin (HlyA), which is expressed and secreted by many UPEC isolates. Here, we demonstrate that HlyA can potently inhibit activation of Akt (protein kinase B), a key regulator of host cell survival, inflammatory responses, proliferation, and metabolism. HlyA ablates Akt activation via an extracellular calcium-dependent, potassium-independent process requiring HlyA insertion into the host plasma membrane and subsequent pore formation. Inhibitor studies indicate that Akt inactivation by HlyA involves aberrant stimulation of host protein phosphatases. We found that two other bacterial pore-forming toxins (aerolysin from Aeromonas species and ␣-toxin from Staphylococcus aureus) can also markedly attenuate Akt activation in a dose-dependent manner. These data suggest a novel mechanism by which sublytic concentrations of HlyA and other pore-forming toxins can modulate host cell survival and inflammatory pathways during the course of a bacterial infection. INTRODUCTIONStrains of uropathogenic Escherichia coli (UPEC) are the leading cause of urinary tract infections (UTIs), which currently rank among the most common of infectious diseases worldwide (Foxman, 2003;Marrs et al., 2005). During the course of an infection, UPEC can stimulate a number of antimicrobial, proinflammatory, prodifferentiation, proliferation, and host cell death pathways (Mulvey, 2002;Mysorekar et al., 2002). In some cases, UPEC can reportedly modulate these signaling events, causing attenuation of host inflammatory responses and potentiating host apoptotic cascades (Klumpp et al., 2001(Klumpp et al., , 2006Hunstad et al., 2005;Billips et al., 2007). These phenomena have been linked in part to the suppression of nuclear factor-B (NF B) activation and downstream signaling by unknown factors associated with UPEC (Klumpp et al., 2001;Hunstad et al., 2005). By hindering host cytokine expression and ensuing inflammatory responses, UPEC may be better able to establish itself and multiply within the cells and tissues of the urinary tract. At the same time, UPEC-induced death of bladder and renal epithelial cells can compromise mucosal barriers, and it may thereby facilitate bacterial dissemination and persistence within the urinary tract (Mulvey et al., 1998Chen et al., 2003a;Bower et al., 2005;Eto et al., 2006;Mansson et al., 2007b).A key regulator of host cell survival pathways is Akt (also known as protein kinase B, PKB; for recent reviews, see Fayard et al., 2005;Song et al., 2005;Manning and Cantley, 2007). This serine/threonine kinase is able to inhibit apoptosis, and it can help control cell cycle and metabolic pathways, endocytosis and vesicular trafficking, and host inflammatory responses, including the activation of NF B. Akt is activated downstream of phosphoinositide 3-kinase (PI3-kinase), which it...

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The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt

Cited by 215 publications

References 58 publications

The Salmonella-containing vacuole—Moving with the times

The Salmonella-containing vacuole—Moving with the times

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

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

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