Many pathogens deliver virulence factors or effectors into host cells in order to evade host defenses and establish infection. Although such effector proteins disrupt critical cellular signaling pathways, they also trigger specific antipathogen responses, a process termed “effector-triggered immunity.” The Gram-negative bacterial pathogen Yersinia inactivates critical proteins of the NF-κB and MAPK signaling cascade, thereby blocking inflammatory cytokine production but also inducing apoptosis. Yersinia-induced apoptosis requires the kinase activity of receptor-interacting protein kinase 1 (RIPK1), a key regulator of cell death, NF-κB, and MAPK signaling. Through the targeted disruption of RIPK1 kinase activity, which selectively disrupts RIPK1-dependent cell death, we now reveal that Yersinia-induced apoptosis is critical for host survival, containment of bacteria in granulomas, and control of bacterial burdens in vivo. We demonstrate that this apoptotic response provides a cell-extrinsic signal that promotes optimal innate immune cytokine production and antibacterial defense, demonstrating a novel role for RIPK1 kinase–induced apoptosis in mediating effector-triggered immunity to circumvent pathogen inhibition of immune signaling.

许多病原体将毒力因子或效应子传递到宿主细胞中，以逃避宿主防御并建立感染。尽管这种效应蛋白破坏了关键的细胞信号传导途径，但它们也触发了特定的抗病原体反应，这一过程称为“效应子触发的免疫力”。革兰氏阴性细菌病原体耶尔森氏菌可灭活NF-κB和MAPK信号级联反应的关键蛋白，从而阻断炎症性细胞因子的产生，但也诱导细胞凋亡。耶尔森氏菌诱导的凋亡需要受体相互作用蛋白激酶1（RIPK1）的激酶活性，RIPK1是细胞死亡，NF-κB和MAPK信号传导的关键调节剂。通过有针对性地破坏RIPK1激酶活性，从而有选择地破坏RIPK1依赖性细胞死亡，我们现在揭示耶尔森氏菌诱导的凋亡对于宿主存活，肉芽肿中细菌的包容和体内细菌负荷的控制至关重要。我们证明，这种凋亡反应提供了一种细胞外源信号，可促进最佳的先天免疫细胞因子产生和抗菌防御，证明了RIPK1激酶诱导的细胞凋亡在介导效应子触发的免疫反应中规避病原体对免疫信号的抑制作用。