Peterson Lance W, Philip Naomi H, DeLaney Alexandra, Wynosky-Dolfi Meghan A, Asklof Kendra, Gray Falon, Choa Ruth, Bjanes Elisabet, Buza Elisabeth L, Hu Baofeng, Dillon Christopher P, Green Douglas R, Berger Scott B, Gough Peter J, Bertin John, Brodsky Igor E
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA.
Institue for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
J Exp Med. 2017 Nov 6;214(11):3171-3182. doi: 10.1084/jem.20170347. Epub 2017 Aug 30.
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 inactivates critical proteins of the NF-κB and MAPK signaling cascade, thereby blocking inflammatory cytokine production but also inducing apoptosis. -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 -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蛋白输送到宿主细胞中，以逃避宿主防御并建立感染。尽管这些效应蛋白会破坏关键的细胞信号通路，但它们也会引发特定的抗病原体反应，这一过程被称为“效应子触发的免疫”。革兰氏阴性细菌病原体使NF-κB和MAPK信号级联的关键蛋白失活，从而阻断炎性细胞因子的产生，但也会诱导细胞凋亡。[病原体名称]诱导的细胞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信号的关键调节因子。通过有针对性地破坏RIPK1激酶活性，选择性地破坏RIPK1依赖性细胞死亡，我们现在发现[病原体名称]诱导的细胞凋亡对于宿主存活、将细菌限制在肉芽肿中以及控制体内细菌负荷至关重要。我们证明这种凋亡反应提供了一种细胞外信号，可促进最佳的先天性免疫细胞因子产生和抗菌防御，这表明RIPK1激酶诱导的细胞凋亡在介导效应子触发的免疫以规避病原体对免疫信号的抑制方面具有新作用。
