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<p>Cell-autonomous immunity represents evolutionarily conserved defense mechanisms present in both immune and non-immune cells. One of such mechanisms is mediated by cytoskeletal septins that entrap cytosolic bacterial pathogens within cage-like structures. To promote infection, <i>Shigella flexneri</i> delivers effector proteins directly into host cells via a type III secretion system. Here we demonstrate that OspC effectors enable <i>Shigella flexneri</i> to evade septin cage entrapment. Mechanistically, OspC catalyzes ADP-riboxanation of SEPT9 at Arg561, a site essential for stabilizing septin hetero-oligomers. Notably, Arg561 ADP-riboxanation impairs septin polymerization and hence assembly of higher-order structures, including filaments and cage-like structures. Furthermore, we provide evidence that OspC effectors act synergistically with OspG to antagonize septin cage entrapment via two distinct post-translational modifications, thereby facilitating cell-to-cell spread and intracellular replication. Overall, our work reveals the elegant strategies of bacterial pathogens to evade septin-mediated cell-autonomous immunity and offers avenues for therapeutic intervention.</p>

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Shigella flexneri evades septin-mediated cell-autonomous immunity via protein ADP-riboxanation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月27日

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  • Zhiheng Tang,
  • Wei Xian,
  • Gizem Özbaykal Güler,
  • Hanyu Zhang,
  • Ying Wang,
  • Naizheng Zhan,
  • Huwei Liu,
  • Fuping You,
  • Qinghua Zou,
  • Serge Mostowy,
  • Xiaoyun Liu

摘要

Cell-autonomous immunity represents evolutionarily conserved defense mechanisms present in both immune and non-immune cells. One of such mechanisms is mediated by cytoskeletal septins that entrap cytosolic bacterial pathogens within cage-like structures. To promote infection, Shigella flexneri delivers effector proteins directly into host cells via a type III secretion system. Here we demonstrate that OspC effectors enable Shigella flexneri to evade septin cage entrapment. Mechanistically, OspC catalyzes ADP-riboxanation of SEPT9 at Arg561, a site essential for stabilizing septin hetero-oligomers. Notably, Arg561 ADP-riboxanation impairs septin polymerization and hence assembly of higher-order structures, including filaments and cage-like structures. Furthermore, we provide evidence that OspC effectors act synergistically with OspG to antagonize septin cage entrapment via two distinct post-translational modifications, thereby facilitating cell-to-cell spread and intracellular replication. Overall, our work reveals the elegant strategies of bacterial pathogens to evade septin-mediated cell-autonomous immunity and offers avenues for therapeutic intervention.