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<p>It remains unclear for the role of microtubule-associated proteins or signaling in necroptosis. Here, we conducted high-throughput screening using a cytoskeleton compound library and identified that release of guanine nucleotide exchange factor-H1 (GEF-H1) upon microtubule destabilization triggers necroptosis. Immunoprecipitation and mass spectrometry revealed that GEF-H1 interacts with DExH-Box helicase 9 (DHX9) and protein-protein interaction network analysis indicated DHX9 is associated with necroptosis. Deficiency of either GEF-H1 or DHX9 significantly inhibits necroptosis. Mechanistically, upon microtubule destabilization, GEF-H1 is translocated to the nucleus and recruits DHX9 and RNA Pol II to the Z-DNA binding protein 1 (ZBP1) promoter region. Subsequently, increasing expression of ZBP1 drives necroptosis. In addition, GEF-H1 signaling upon microtubule destabilization also plays a positive role in lipopolysaccharide-induced cell death and inflammation. Collectively, these findings uncover an important role for GEF-H1 signaling in necroptosis and inflammation.</p><p></p>

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GEF-H1 upon microtubule destabilization drives ZBP1-dependent necroptosis

  • 期刊论文

  • 发表日期：

    2026年3月17日

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  • Xufei Zhang,
  • Xuanheng Li,
  • Yiyu Yang,
  • Jie Wu,
  • Qinjie Liu,
  • Liting Deng,
  • Jinjian Huang,
  • Yun Zhao,
  • Jianan Ren,
  • Xiuwen Wu

摘要

It remains unclear for the role of microtubule-associated proteins or signaling in necroptosis. Here, we conducted high-throughput screening using a cytoskeleton compound library and identified that release of guanine nucleotide exchange factor-H1 (GEF-H1) upon microtubule destabilization triggers necroptosis. Immunoprecipitation and mass spectrometry revealed that GEF-H1 interacts with DExH-Box helicase 9 (DHX9) and protein-protein interaction network analysis indicated DHX9 is associated with necroptosis. Deficiency of either GEF-H1 or DHX9 significantly inhibits necroptosis. Mechanistically, upon microtubule destabilization, GEF-H1 is translocated to the nucleus and recruits DHX9 and RNA Pol II to the Z-DNA binding protein 1 (ZBP1) promoter region. Subsequently, increasing expression of ZBP1 drives necroptosis. In addition, GEF-H1 signaling upon microtubule destabilization also plays a positive role in lipopolysaccharide-induced cell death and inflammation. Collectively, these findings uncover an important role for GEF-H1 signaling in necroptosis and inflammation.