Abstract
SopB is a type 3 secreted effector with phosphatase activity that Salmonella employs to manipulate host cellular processes, allowing the bacteria to establish their intracellular niche. One important function of SopB is activation of the pro-survival kinase Akt/protein kinase B in the infected host cell. Here, we examine the mechanism of Akt activation by SopB during Salmonella infection. We show that SopB-mediated Akt activation is only partially sensitive to PI3-kinase inhibitors LY294002 and wortmannin in HeLa cells, suggesting that Class I PI3-kinases play only a minor role in this process. However, depletion of PI(3,4) P2/PI(3–5) P3 by expression of the phosphoinositide 3-phosphatase PTEN inhibits Akt activation during Salmonella invasion. Therefore, production of PI(3,4) P2/PI(3–5) P3 appears to be a necessary event for Akt activation by SopB and suggests that non-canonical kinases mediate production of these phosphoinositides during Salmonella infection. We report that Class II PI3-kinase beta isoform, IPMK and other kinases identified from a kinase screen all contribute to Akt activation during Salmonella infection. In addition, the kinases required for SopB-mediated activation of Akt vary depending on the type of infected host cell. Together, our data suggest that Salmonella has evolved to use a single effector, SopB, to manipulate a remarkably large repertoire of host kinases to activate Akt for the purpose of optimizing bacterial replication in its host.
Highlights
We observed that cells transfected with plasmids expressing SopB showed significant increase in Akt activation compared to control
We believe that such differences in sensitivity may be cell-type dependent, since we saw a significant decrease in SopBmediated Akt activation when Salmonella-infected embryonic stem cells or mouse embryonic fibroblasts were treated with LY294002
Our findings and that of Cooper et al suggest that the mechanisms of Akt activation by Salmonella vary depending on the cell types used for infection
Summary
Typhimurium) is a major cause of food poisoning worldwide and infections can be lethal in young children or immunocompromised hosts [1,2]. These bacteria have the ability to invade host cells and grow intracellularly. Typhimurium uses type 3 secretion systems (T3SS) to translocate effector proteins directly into host cells [3]. The T3SS effectors activate signal transduction pathways leading to actin rearrangements that drive internalization of the bacteria into membrane-bound compartments, known as Salmonella-containing vacuoles (SCVs), within which the bacteria can survive and replicate [4,5]. One T3SS effector, SopB, is known to contribute to S. SopB contributes to other important phenotypes associated with infection, including production of proinflammatory cytokines [7], controlling SCV maturation [8], intracellular positioning of the SCV [9], blocking apoptosis [10], intracellular bacterial replication [8] and induction of epithelial-mesenchymal transition [11]
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