ArticleCell death and differentiation2026
GEF-H1 upon microtubule destabilization drives ZBP1-dependent necroptosis.
Article in Cell death and differentiation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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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