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/immune crosstalk. Bacterial effectors manipulate host physiology
through diverse mechanisms. Here, Gibbs et al . demonstrate that the secreted Salmonella
SarA/SteE effector shares sequence and function with the gp130 cytokine receptor’s
intracellular domain. Through a tyrosine-phosphorylated YxxQ motif and recruitment
of STAT3 and GSK-3, SarA forms a STAT3-activating complex to reprogram host transcription.