Mechanism and plasticity of primitive pyroptosis
- Zhi Su
- Man Huang
- Jianhua Gan
- Zhaoxiang He
- Yuanyuan Wang
- Yuanwei Zhang
- Jiuxin Qu
- Long Zhou
- Changbin Chen
- Yu Feng
- Zheng-Guo He
- Youjun Feng
2026-08-14
Pyroptosis is a proinflammatory form of regulated cell death across the tree of life. The gasdermin (GSDM) protein family functions as an evolutionarily conserved executioner of pyroptotic cell death by forming membrane pores. As the canonical activation mechanism, proteolytic cleavage drives the formation of GSDM pores. In contrast to the well-studied modern GSDM-directed pyroptotic pathway, biochemical mechanisms of primitive GSDM pores are poorly understood. Here, we functionally characterize two primitive GSDM variants with cytotoxicity, one of which is a bacterial homolog (termed bGSDM) from Runella zeae , and the other refers to a fungal homolog (fGSDM/HET-Q1) of Podospora anserina . The cleavage of bGSDM (or fGSDM/HET-Q1) by two distantly related proteases enables the in vitro reconstitution of GSDM progenitor-gated pyroptotic pores on liposome. In particular, we present high-resolution cryo–electron microscopy structures of two primitive pyroptotic pores, consisting of a Runella bGSDM ring at 3.25 angstroms and a Podospora fGSDM pore at 2.68 angstroms. Unlike the large bGSDM pore arranged in 46-fold symmetry, the smallest fGSDM pore is composed of 20 HET-Q1 protomers. Structure-to-function studies illuminate how bGSDM/fGSDM protomers assemble into distinct membrane pores. We also investigate the feasibility of engineering primitive GSDM pores to counter top-priority bacterial/fungal pathogens. Collectively, our findings offer a primitive mechanism for lytic cell death executed by flexible pores.