Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization

Abstract

Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an antiinflammatory transcriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylation of SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Ra (IL-4Ra). Overall, the conversion of GSK3 to a tyrosine-directed kinase represents a tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment.

A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation

“…These results show that GSK3 is a central regulator of the balanced host response during infection, and that targeting GSK3 function is likely to make the host susceptible to disease. In line with this prediction, GSK3 was recently found to be co-opted by the Salmonella enterica serovar Typhimurium effector SteE to skew infected macrophage polarization and allow infection to persist(65,66). Our results suggest another possible effect of targeting GSK3 may be the inefficient upregulation of MHCII on Salmonella-infected macrophages in response to IFNg.…”

Innate Activation of IFN-γ—iNOS Axis During Infection With Salmonella Represses the Ability of T Cells to Produce IL-2

“…Salmonella has evolved many strategies to counter or evade immune responses during establishment of infection. However, while the modulation of innate immune responses during infection with this pathogen is well studied (21)(22)(23)(24), the strategies which Salmonella employs to evade T-cell-mediated immune responses have not been investigated in detail (25)(26)(27). Salmonella has been shown to inhibit CD4 T cell activation in vitro by bringing about downregulation of the T cell receptor and by inducing negative modulators of T cell activation (28)(29)(30).…”

“…It has also been shown to inhibit antigen processing and presentation from dendritic cells in vitro (31). The effectors of Salmonella pathogenicity island -2 (SPI-2) have been reported to suppress migration of dendritic cells to the site of infection, downregulate CD4 and CD8 T cell responses and polarize macrophage functions (23,24,32,33). However, the exact mechanism by which this pathogen modulates T cell responses during in vivo infection and the interplay of T cells with other immune cells particularly mononuclear phagocytes which host Salmonella during in vivo infection remain poorly understood.…”

IntracellularCryptococcus neoformansdisrupts the transcriptome profile of M1- and M2-polarized host macrophages

“…While these changes are largely driven by the milieu of cytokines and inflammatory regulators present within the microenvironment of the cell, a broad range of pathogens are known to subvert this process as part of intracellular survival strategies [17]. For example, the bacterial pathogen Salmonella enterica serovar Typhimurium ( S. Typhimurium) utilizes secreted effectors to alter the activity of host cell STAT3 signaling to promote repolarization to an M2-like state [53, 54], creating an environment more permissive for intracellular survival.…”