Abstract
SummaryMany 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 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-4Rα (IL-4Rα). 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.
Highlights
The delivery of effector proteins into host cells enables pathogenesis of Salmonella enterica serovar Typhimurium
It is known that Salmonella activates signal transducer and activator of transcription 3 (STAT3) in macrophages (Lin and Bost, 2004), but only recently was SteE identified as the key effector responsible (Jaslow et al, 2018)
Salmonella-Mediated M2 Macrophage Polarization Is SteE and STAT3 Dependent Infection of primary bone-marrow-derived macrophages by Salmonella Typhimurium polarizes cells into an anti-inflammatory M2-like state that is dependent on SteE (Stapels et al, 2018)
Summary
The delivery of effector proteins into host cells enables pathogenesis of Salmonella enterica serovar Typhimurium. SteE ( referred to as STM2585 or SarA) stimulates the production of a key anti-inflammatory cytokine, interleukin (IL-10), by activating the host transcription factor signal transducer and activator of transcription 3 (STAT3) (Jaslow et al, 2018). After stimulation with cytokines such as IL-6 and IL-10, cytoplasmic STAT3 becomes phosphorylated on Y705 (Darnell et al, 1994; Schindler and Darnell, 1995). This results in STAT3 homodimerization, nuclear translocation, and expression of anti-inflammatory genes. It is known that Salmonella activates STAT3 in macrophages (Lin and Bost, 2004), but only recently was SteE identified as the key effector responsible (Jaslow et al, 2018). SteE interacts with STAT3, the mechanism driving STAT3 activation remains unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
