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

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          Summary

          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.

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          eTOC

          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
          101302316
          33345
          Cell Host Microbe
          Cell Host Microbe
          Cell host & microbe
          1931-3128
          1934-6069
          4 December 2019
          31 December 2019
          08 January 2020
          08 January 2021
          : 27
          : 1
          : 129-139.e4
          Affiliations
          [1 ]Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
          [2 ]Department of Biochemistry, School of Medicine, Duke University, Durham, NC 27710, USA
          [3 ]Duke University Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA
          [4 ]Duke Proteomics and Metabolomics Shared Resource, Duke University Medical Center, Durham, NC 27710, USA
          [5 ]Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA
          [6 ]Lead contact
          Author notes
          [* ]To whom correspondence should be addressed: Dennis C. Ko, 0049 CARL Building Box 3053, 213 Research Drive, Durham, NC 27710. 919-684-5834. dennis.ko@ 123456duke.edu . @denniskoHiHOST

          Author Contributions

          All authors critically reviewed the manuscript and contributed input to the final submission. KDG, EJW, JSB, MWF, and DCK wrote the manuscript. KDG, EJW, SLJ, RGB, and DCK contributed to strategy and project planning. All authors carried out experiments and analysis.

          Article
          PMC6952535 PMC6952535 6952535 nihpa1545165
          10.1016/j.chom.2019.11.012
          6952535
          31901521
          a673228f-3724-4507-935c-33547db01fb2
          History
          Categories
          Article

          SH2,SOCS-3,GSK-3,parallel reaction monitoring,gp130,PRM,YxxQ,JAK-STAT,cytokine receptor,SPI-2

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