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<p>GSDMD is a pyroptosis executioner in which the C-terminal domain completely inhibits the pore-forming ability of the N-terminal domain. Caspase cleavage separates GSDMD into the free C-terminal fragment (GD-CT) and the free N-terminal fragment (GD-NT). Although GD-CT retains the ability to bind with GD-NT, it can no longer completely disable GD-NT, allowing the latter to oligomerize and form nano-sized pyroptotic pores in the plasma membrane. In this study, we report that GD-CT is strictly confined to the cytoplasm, whereas GD-NT is transported to the plasma membrane. Additionally, GD-CT undergoes rapid degradation via the 26S proteasome pathway. Therefore, we propose that the spatial separation and rapid turnover of GD-CT limit its efficacy in blocking GD-NT-mediated pyroptosis. Given these properties of GD-CT, we engineered an efficient pyroptosis blocker “FKBP-GD-CT”. This chimera protein incorporates a myristoylation motif, which confers plasma membrane translocation capability, and an FKBP12F36V domain, which enables dimerization in response to the chemical inducer AP20187. This is the first report utilizing chemical-induced dimerization technology to modulate pyroptosis levels.</p><p></p>

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Chemically induced dimerization of GSDMD C-terminal domain blocks GSDMD N-terminal domain-mediated pyroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月13日

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  • Jixuan Xu,
  • Miaoran Fu,
  • Yamin Xing,
  • Wulong Liang,
  • Guangyuan Li,
  • Ting Zhang,
  • Mengxue Li,
  • Chunxiao Gao,
  • Zhanfeng Yang,
  • Yuming Fu,
  • Min Zhang,
  • Zisen Zhang,
  • Pengyuan Zheng,
  • Xiufeng Chu

摘要

GSDMD is a pyroptosis executioner in which the C-terminal domain completely inhibits the pore-forming ability of the N-terminal domain. Caspase cleavage separates GSDMD into the free C-terminal fragment (GD-CT) and the free N-terminal fragment (GD-NT). Although GD-CT retains the ability to bind with GD-NT, it can no longer completely disable GD-NT, allowing the latter to oligomerize and form nano-sized pyroptotic pores in the plasma membrane. In this study, we report that GD-CT is strictly confined to the cytoplasm, whereas GD-NT is transported to the plasma membrane. Additionally, GD-CT undergoes rapid degradation via the 26S proteasome pathway. Therefore, we propose that the spatial separation and rapid turnover of GD-CT limit its efficacy in blocking GD-NT-mediated pyroptosis. Given these properties of GD-CT, we engineered an efficient pyroptosis blocker “FKBP-GD-CT”. This chimera protein incorporates a myristoylation motif, which confers plasma membrane translocation capability, and an FKBP12F36V domain, which enables dimerization in response to the chemical inducer AP20187. This is the first report utilizing chemical-induced dimerization technology to modulate pyroptosis levels.