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. Author manuscript; available in PMC: 2025 Aug 27.
Published in final edited form as: Nat Immunol. 2023 Jun 5;24(7):1064–1075. doi: 10.1038/s41590-023-01526-w

Fig. 3 |. Evolutionary history of the GSDM protein family.

Fig. 3 |

a, All GSDMs are likely derived from one common ancestor. This pore-forming proto-GSDM diversified to give rise to all GSDM proteins known today in prokaryotes, fungi and metazoans. GSDME is the most ancient GSDM found in metazoans. Gene duplications in early vertebrates, amniotes and mammals resulted in the genes encoding pejvakin, GSDMA and GSDMB/GSDMC/GSDMD, respectively. GSDMs appear to be absent from plants and ecdysozoa (such as insects and nematodes). b, GSDMs from various kingdoms of life can be activated by proteolysis. GSDMs found in metazoans are typically cleaved by proteases such as caspases or granzymes upon pathogen infection. Fungal GSDMs (such as HET-Q1), which are involved in allorecognition, can be cleaved and activated by subtilisin-like proteases (such as HET-Q2). bGSDMs can be cleaved, for example, by caspase-like CHAT proteases, which are activated in response to phage infection. Proteolytic cleavage of these diverse GSDMs leads to membrane pore formation and cell death.