Ashida Hiroshi, Okano Tokuju, Iida Tamako, Onsoi Poramed, Sasakawa Chihiro, Suzuki Toshihiko
Department of Bacterial Infection and Host Response, Graduate School of Medical and Dental Sciences, Institute of SCIENCE TOKYO, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8673, Japan.
EMBO J. 2025 Sep 10. doi: 10.1038/s44318-025-00561-7.
Many enteric bacterial pathogens deliver virulence effectors to counteract host innate immune responses, such as inflammation and cell death, and colonize the intestinal epithelium. However, host cells recognize the disruption of their innate immune signaling by bacterial effectors and induce alternative immune responses, collectively termed "effector-triggered immunity", to clear bacterial pathogens. Here, we describe a mechanism of cell death induction via effector-triggered immunity and the bacterial countermeasures of the pathogen Shigella flexneri. Shigella delivers the OspI effector to inhibit NF-κB activation, which results in caspase-8 activation in return. Deamidation and inactivation of the E2 ubiquitin-conjugating enzyme Ubc13 by OspI results in the inactivation of cIAPs, which serves as a cue to trigger apoptosis and necroptosis. To prevent caspase-8-mediated apoptosis, Shigella delivers OspC1 and inhibits caspase-8 activation via its ADP-riboxanation activity, which however triggers necroptosis. Necroptosis induced as a secondary effector-triggered immunity response by OspC1 is eventually prevented by another Shigella effector, OspD3. The findings of this study reveal a complex multilayered bacterial strategy for circumventing host cell death induction via effector-triggered immunity.
许多肠道细菌病原体递送毒力效应蛋白以对抗宿主的固有免疫反应，如炎症和细胞死亡，并在肠道上皮细胞中定殖。然而，宿主细胞识别细菌效应蛋白对其固有免疫信号的破坏，并诱导替代性免疫反应，统称为“效应蛋白触发的免疫”，以清除细菌病原体。在此，我们描述了一种通过效应蛋白触发的免疫诱导细胞死亡的机制以及病原体福氏志贺菌的细菌应对措施。志贺菌递送OspI效应蛋白以抑制NF-κB激活，这反过来导致半胱天冬酶-8激活。OspI对E2泛素缀合酶Ubc13的脱酰胺作用和失活导致cIAPs失活，这作为触发凋亡和坏死性凋亡的信号。为了防止半胱天冬酶-8介导的凋亡，志贺菌递送OspC1并通过其ADP-核糖基化活性抑制半胱天冬酶-8激活，然而这会触发坏死性凋亡。由OspC1作为效应蛋白触发的免疫反应的次级反应诱导的坏死性凋亡最终被另一种志贺菌效应蛋白OspD3阻止。本研究的结果揭示了一种复杂的多层细菌策略，用于通过效应蛋白触发的免疫规避宿主细胞死亡诱导。
