Chen Kaiwen W, Demarco Benjamin, Ramos Saray, Heilig Rosalie, Goris Michiel, Grayczyk James P, Assenmacher Charles-Antoine, Radaelli Enrico, Joannas Leonel D, Henao-Mejia Jorge, Tacchini-Cottier Fabienne, Brodsky Igor E, Broz Petr
Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland;
Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456.
Proc Natl Acad Sci U S A. 2021 Jul 13;118(28). doi: 10.1073/pnas.2101189118.
Injection of effector proteins to block host innate immune signaling is a common strategy used by many pathogenic organisms to establish an infection. For example, pathogenic species inject the acetyltransferase YopJ into target cells to inhibit NF-κB and MAPK signaling. To counteract this, detection of YopJ activity in myeloid cells promotes the assembly of a RIPK1-caspase-8 death-inducing platform that confers antibacterial defense. While recent studies revealed that caspase-8 cleaves the pore-forming protein gasdermin D to trigger pyroptosis in macrophages, whether RIPK1 activates additional substrates downstream of caspase-8 to promote host defense is unclear. Here, we report that the related gasdermin family member gasdermin E (GSDME) is activated upon detection of YopJ activity in a RIPK1 kinase-dependent manner. Specifically, GSDME promotes neutrophil pyroptosis and IL-1β release, which is critical for anti- defense. During in vivo infection, IL-1β neutralization increases bacterial burden in wild-type but not -deficient mice. Thus, our study establishes GSDME as an important mediator that counteracts pathogen blockade of innate immune signaling.
注射效应蛋白以阻断宿主固有免疫信号传导是许多致病生物建立感染所采用的常见策略。例如，致病菌将乙酰转移酶YopJ注入靶细胞以抑制NF-κB和MAPK信号传导。为了应对这种情况，在髓样细胞中检测YopJ活性会促进RIPK1-半胱天冬酶-8死亡诱导平台的组装，从而赋予抗菌防御能力。虽然最近的研究表明半胱天冬酶-8切割成孔蛋白gasdermin D以触发巨噬细胞中的焦亡，但RIPK1是否激活半胱天冬酶-8下游的其他底物以促进宿主防御尚不清楚。在这里，我们报告相关的gasdermin家族成员gasdermin E（GSDME）在以RIPK1激酶依赖性方式检测到YopJ活性后被激活。具体而言，GSDME促进中性粒细胞焦亡和IL-1β释放，这对抗防御至关重要。在体内感染期间，IL-1β中和增加野生型小鼠而非缺陷型小鼠的细菌负荷。因此，我们的研究将GSDME确立为对抗病原体对固有免疫信号传导阻断的重要介质。
