The pore-forming protein gasdermin D (GSDMD) executes lytic cell death called pyroptosis to eliminate the replicative niche of intracellular pathogens. Evolution favors pathogens that circumvent this host defense mechanism. Here, we show that the Shigella ubiquitin ligase IpaH7.8 functions as an inhibitor of GSDMD. Shigella is an enteroinvasive bacterium that causes hemorrhagic gastroenteritis in primates, but not rodents. IpaH7.8 contributes to species specificity by ubiquitinating human, but not mouse, GSDMD and targeting it for proteasomal degradation. Accordingly, infection of human epithelial cells with IpaH7.8-deficient Shigella flexneri results in increased GSDMD-dependent cell death compared with wild type. Consistent with pyroptosis contributing to murine disease resistance, eliminating GSDMD from NLRC4-deficient mice, which are already sensitized to oral infection with Shigella flexneri, leads to further enhanced bacterial replication and increased disease severity. This work highlights a species-specific pathogen arms race focused on maintenance of host cell viability.

成孔蛋白 gasdermin D (GSDMD) 执行称为细胞焦亡的裂解细胞死亡，以消除细胞内病原体的复制生态位。进化有利于绕过这种宿主防御机制的病原体。在这里，我们展示了志贺氏菌泛素连接酶 IpaH7.8 作为 GSDMD 的抑制剂。志贺氏菌是一种肠侵袭性细菌，可在灵长类动物中引起出血性胃肠炎，但在啮齿动物中不会。IpaH7.8 通过泛素化人类而非小鼠 GSDMD 并将其靶向蛋白酶体降解来促进物种特异性。因此，用 IpaH7.8 缺陷型福氏志贺氏菌感染人上皮细胞与野生型相比，导致 GSDMD 依赖性细胞死亡增加。与导致小鼠抗病性的细胞焦亡一致，从已经对福氏志贺氏菌口腔感染敏感的 NLRC4 缺陷小鼠中消除 GSDMD会导致细菌复制进一步增强并增加疾病严重程度。这项工作突出了一种以维持宿主细胞活力为重点的物种特异性病原体军备竞赛。