GEF-H1 upon microtubule destabilization drives ZBP1-dependent necroptosis

  • Cell Death Differ. 2026 Mar 17. doi: 10.1038/s41418-026-01711-y.
Xufei Zhang  #  1  2 ,  Xuanheng Li  #  3 ,  Yiyu Yang  #  2 ,  Jie Wu  4 ,  Qinjie Liu  5 ,  Liting Deng  2 ,  Jinjian Huang  3 ,  Yun Zhao  6 ,  Jianan Ren  7  8 ,  Xiuwen Wu  9  10
Affiliations
  • 1. Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 2. Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, China.
  • 3. Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 4. Department of Critical Care Medicine, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
  • 5. Department of General Surgery, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
  • 6. Research Center of Surgery, BenQ Medical Center, the Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China. [email protected].
  • 7. Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, China. [email protected].
  • 8. Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. [email protected].
  • 9. Research Institute of General Surgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, China. [email protected].
  • 10. Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 41844895 DOI: 10.1038/s41418-026-01711-y
Abstract

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.

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