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<p>Macrophage infection by the pathogenic bacteria <i>Yersinia</i> or mimic stimulation of lipopolysaccharide (LPS) and transforming growth factor-β-activated kinase 1 (TAK1) inhibitor or tumor necrosis factor (TNF) and TAK1 inhibitor induces caspase-8-mediated gasdermin D (GSDMD) cleavage and pyroptosis. However, the upstream regulator of caspase-8-dependent cleavage of GSDMD remains elusive. Here we show that Serine/threonine-protein kinase RIO2 (RIOK2) interacts with the Fas-associated protein with death domain (FADD) and is essential for caspase-8-driven GSDMD cleavage. RIOK2’s kinase activity drives the transport of lysosome to ER through activating myosin II and thereby translocate FADD-RIPK1-caspase-8 complex from lysosome to ER. Importantly, RIOK2’s ATPase activity enhances its binding to this complex and directly triggers caspase-8 and gasdermin D cleavage both at ER and in vitro. Furthermore, RIOK2-mediated pyroptosis enhances host defense against <i>Yersinia</i> infection. Thus, our findings define an upstream regulator of caspase-8-dependent pyroptosis, implying a role of organelle crosstalk in spatial cleavage of gasdermins.</p>

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RIOK2 kinase regulates the translocation of the FADD–RIPK1–Caspase-8 complex to the ER and the cleavage of Gasdermin D to drive pyroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • Mingtong Ma,
  • Fei Wang,
  • Pengfei Cui,
  • Yingying Zhang,
  • Hanyu Ma,
  • Yifan He,
  • Yuanna Cheng,
  • Jingping Huang,
  • Jingxiang Wang,
  • Xiangyang Wu,
  • Hua Yang,
  • Ruijuan Zheng,
  • Haowen Ma,
  • Qian Cai,
  • Lin Wang,
  • Baoxue Ge

摘要

Macrophage infection by the pathogenic bacteria Yersinia or mimic stimulation of lipopolysaccharide (LPS) and transforming growth factor-β-activated kinase 1 (TAK1) inhibitor or tumor necrosis factor (TNF) and TAK1 inhibitor induces caspase-8-mediated gasdermin D (GSDMD) cleavage and pyroptosis. However, the upstream regulator of caspase-8-dependent cleavage of GSDMD remains elusive. Here we show that Serine/threonine-protein kinase RIO2 (RIOK2) interacts with the Fas-associated protein with death domain (FADD) and is essential for caspase-8-driven GSDMD cleavage. RIOK2’s kinase activity drives the transport of lysosome to ER through activating myosin II and thereby translocate FADD-RIPK1-caspase-8 complex from lysosome to ER. Importantly, RIOK2’s ATPase activity enhances its binding to this complex and directly triggers caspase-8 and gasdermin D cleavage both at ER and in vitro. Furthermore, RIOK2-mediated pyroptosis enhances host defense against Yersinia infection. Thus, our findings define an upstream regulator of caspase-8-dependent pyroptosis, implying a role of organelle crosstalk in spatial cleavage of gasdermins.