The Salmonella Secreted Effector SarA/SteE Mimics Cytokine Receptor Signaling to Activate STAT3.

Bacteria masterfully co-opt and subvert host signal transduction. As a paradigmatic example, Salmonella uses two type-3 secretion systems to inject effector proteins that facilitate Salmonella entry, establishment of an intracellular niche, and modulation of immune responses. We previously demonstrated that the Salmonella anti-inflammatory response activator SarA (Stm2585, GogC, PagJ, SteE) activates the host transcription factor STAT3 to drive expression of immunomodulatory STAT3-targets. Here, we demonstrate-by sequence, function, and biochemical measurement-that SarA mimics the cytoplasmic domain of glycoprotein 130 (gp130, IL6ST). SarA is phosphorylated at a YxxQ motif, facilitating binding to STAT3 with greater affinity than gp130. Departing from canonical gp130 signaling, SarA function is JAK-independent but requires GSK-3, a key regulator of metabolism and development. Our results reveal that SarA undergoes host phosphorylation to recruit a STAT3-activating complex, circumventing cytokine receptor activation. Effector mimicry of gp130 suggests GSK-3 can regulate normal cytokine signaling, potentially enabling metabolic and immune crosstalk.

Duke Scholars

Author Erica Washington Molecular Genetics and Microbiology

Author Matthew Wolf Foster Medicine, Pulmonary, Allergy, and Critical Care Medicine

Author Richard Gerald Brennan Biochemistry

Author Dennis Ko Molecular Genetics and Microbiology