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<p>Gasdermins (GSDMs) are pore-forming proteins that mediate pyroptosis and contribute to inflammatory and cancer-related processes. Although GSDME shares structural similarity with other gasdermins, its activation and pore assembly mechanisms remain incompletely defined. Here we determine high-resolution cryo-electron microscopy structures of 27- and 28-fold human GSDME pores at 3.64 Å and 3.58 Å resolution. The structures reveal conserved structural architecture together with distinct features, including an extended transmembrane β-barrel and a comparatively compact membrane-engagement geometry. Structure-guided mutagenesis identifies lipid-binding and oligomerization interfaces required for pore formation. We further demonstrate that caspase-3 activates GSDME through direct recognition of a DMPD tetrapeptide motif within the interdomain linker, independently of the GSDME C-terminal domain. Following proteolytic activation, <i>S</i>-palmitoylation of GSDME N-terminal domain enhances pore-forming efficiency, with Cys180 serving as the primary functional site. Together, these findings establish a coordinated structural and regulatory framework in which proteolytic licensing and lipid modification sequentially control GSDME pore formation.</p>

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Structural basis and regulation of GSDME pore formation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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  • Evelyn Teran,
  • Tian Tian,
  • Chengliang Wang,
  • Xinzheng Wang,
  • Jinghan Wang,
  • Dongchun Ni,
  • Vijay A. Rathinam,
  • Jianbin Ruan

摘要

Gasdermins (GSDMs) are pore-forming proteins that mediate pyroptosis and contribute to inflammatory and cancer-related processes. Although GSDME shares structural similarity with other gasdermins, its activation and pore assembly mechanisms remain incompletely defined. Here we determine high-resolution cryo-electron microscopy structures of 27- and 28-fold human GSDME pores at 3.64 Å and 3.58 Å resolution. The structures reveal conserved structural architecture together with distinct features, including an extended transmembrane β-barrel and a comparatively compact membrane-engagement geometry. Structure-guided mutagenesis identifies lipid-binding and oligomerization interfaces required for pore formation. We further demonstrate that caspase-3 activates GSDME through direct recognition of a DMPD tetrapeptide motif within the interdomain linker, independently of the GSDME C-terminal domain. Following proteolytic activation, S-palmitoylation of GSDME N-terminal domain enhances pore-forming efficiency, with Cys180 serving as the primary functional site. Together, these findings establish a coordinated structural and regulatory framework in which proteolytic licensing and lipid modification sequentially control GSDME pore formation.