The Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase

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 anti-inflammatory 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 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 STAT3 on tyrosine-705. This results in STAT3 activation and both GSK3 and STAT3 are required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker IL-4Rα. Overall, the conversion of GSK3 to a tyrosine-directed kinase represents an unprecedented example of how a bacterial virulence protein reprograms innate immune signalling to establish an anti-inflammatory environment.