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

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          Abstract

          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.

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          Author and article information

          Journal
          Cell Host & Microbe
          Cell Host & Microbe
          Elsevier BV
          19313128
          January 2020
          January 2020
          : 27
          : 1
          : 129-139.e4
          Article
          10.1016/j.chom.2019.11.012
          6952535
          31901521
          a673228f-3724-4507-935c-33547db01fb2
          © 2020

          https://www.elsevier.com/tdm/userlicense/1.0/

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