Caspase-8 as a focal hub in effector-triggered immunity

Caspase-8 作为效应子触发免疫的焦点

• 批准号: 10614514
• 负责人: Egil Lien
• 金额: $ 58.41万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614514
• 关键词: Address; Apoptotic; Automobile Driving; Bacteria; Bacterial Infections; Biological Models; CASP1 gene; CASP8 gene; CRISPR screen; Cell Death; Cell Death Induction; Cell Maturation; Cell membrane; Cessation of life; Complex; Data; Defense Mechanisms; Event; Experimental Designs; Exposure to; Gastroenteritis; Host Defense; IL18 gene; Immune response; Immune signaling; Immunity; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Interleukin-1 beta; Knowledge; Link; MAP3K7 gene; Macrophage; Mediating; Mediator; Membrane; Modification; Molecular; N-terminal; Pathogenicity; Pathologic; Pathway interactions; Phosphotransferases; Physiological; Plague; Plants; Post-Translational Protein Processing; Process; Proteins; RIPK1 gene; Role; Signal Pathway; Stimulus; System; TNF gene; Type III Secretion System Pathway; Virulence; Yersinia; Yersinia infections; arms race; cytokine; cytotoxic; cytotoxicity; in vivo; innate immune sensing; novel; pathogen; pathogenic bacteria; response

PROJECT SUMMARY/ABSTRACT: Bacterial secretion system effectors are essential for the virulence of many bacterial pathogens, and a number of effector proteins block key immune signaling pathways. However, these effectors or the alterations they cause can also be sensed by the innate immune system. For example, effector mediated modifications of host proteins can be recognized as pathological and trigger immune responses, a process known as effector- triggered immunity (ETI). While ETI was first discovered in plants, it is now clear that ETI is a common defense mechanism that is a major driving factor in the constant arms race between host and pathogens. Knowledge about these processes is central to understanding bacterial virulence as well as host defense. Conventional inflammasomes are multi-molecular complexes that control caspase-1 and/or 11-mediated pyroptotic cell death and maturation of inflammatory cytokines IL-1b/IL-18. Gasdermin D (GSDMD) was recently shown to be a key mediator of inflammasome triggered pyroptosis by cleavage at residue D276 by caspase-1/11, and the released N-terminal fragments create a pore in cell membranes compromising membrane integrity. These pores are also linked to IL-1β and IL-18 release. Infection of macrophages with pathogenic Yersinia spp., causative agents of plague and gastroenteritis, trigger cell death as well as IL-1β/IL- 18 release. We have previously described a novel unconventional inflammasome pathway, requiring RIP1 kinase and caspase-8, which are typically associated with apoptotic death, that control cytokine release and macrophage cytotoxicity after Yersinia infection. Specifically, the Type III secretion system (T3SS) effector YopJ strongly activates caspase-8 and drives this unconventional pathway. Thus, Yersinia is an excellent physiologically relevant model system to investigate the role of caspase-8 in the context of bacterial infection. In particular, our supporting data indicate that YopJ inhibition of TAK1 and IKKβ kinases activates caspase-8 and induces a non-canonical inflammasome pathway, that is not dependent on caspase-1 or -11. Similar responses are observed when inhibiting TAK1 and IKK activity, mimicking YopJ action. We show that GSDMD is cleaved at D276 and activated by Yersinia in a caspase-8 dependent manner and that GSDMD strongly regulates cell death and IL-1β/IL-18 release. These findings lead us to hypothesize that Yersinia YopJ triggers a novel effector-mediated immune response, via RIPK1 and caspase-8, leading to GSDMD cleavage, cell death and IL-1β release. How RIPK1 and caspase-8 are activated and how these events activate GSDMD are critical questions addressed herein

项目摘要/摘要： 细菌分泌系统效应物对许多细菌病原体的毒力是必不可少的，而且许多 效应蛋白阻断了关键的免疫信号通路。然而，这些效应器或它们的改变 原因也可以被先天免疫系统感知到。例如，效应器介导的宿主修改 蛋白质可以被识别为病理性的并触发免疫反应，这一过程被称为效应器- 触发豁免(ETI)。虽然ETI最初是在植物中发现的，但现在很明显，ETI是一种常见的防御措施 这一机制是宿主和病原体之间持续不断的军备竞赛的主要驱动因素。知识 关于这些过程是了解细菌毒力和宿主防御的核心。 传统的炎性小体是控制caspase-1和/或11介导的多分子复合体。 嗜热性细胞死亡与炎性细胞因子IL-1b/IL-18的成熟Gasdermin D(GSDMD)为 最近被证明是通过裂解D276残基引发的炎症体下垂的关键介质 Caspase-1/11和释放的N-末端片段在细胞膜上形成一个孔，损害 膜的完整性。这些毛孔还与IL-1β和IL-18的释放有关。巨噬细胞感染 致病性耶尔森氏菌是鼠疫和胃肠炎的病原体，可触发细胞死亡和IL-1β/IL-1。 18释放。我们之前已经描述了一种新的非传统炎症体途径，需要RIP1 激酶和caspase-8，它们通常与凋亡性死亡有关，它们控制细胞因子的释放和 耶尔森氏菌感染后巨噬细胞的细胞毒性。具体来说，III型分泌系统(T3SS)效应器 YopJ强烈激活caspase-8并驱动这一非常规途径。因此，耶尔西尼亚是一个极好的 生理相关的模型系统，以研究caspase-8在细菌感染中的作用。 特别是，我们的支持数据表明，YopJ抑制tak1和ikkcaspase-8激活β-8。 并诱导不依赖于caspase-1或-11的非典型炎症体途径。类似 当抑制TAK1和IKK活性时，可以观察到类似YopJ作用的反应。我们证明了GSDMD 在D276处被裂解，并被耶尔森氏菌以caspase-8依赖方式激活，GSDMD强烈 调节细胞死亡和IL-1β/IL-18的释放。这些发现使我们假设Yersinia YopJ 通过RIPK1和caspase-8触发一种新的效应器介导的免疫反应，导致GSDMD 卵裂、细胞死亡和IL-1β释放。RIPK1和caspase-8是如何激活的，以及这些事件是如何 激活GSDMD是这里要解决的关键问题

项目成果

Caspase-8 inhibition improves the outcome of bacterial infections in mice by promoting neutrophil activation.

• DOI: 10.1016/j.xcrm.2023.101098
• 发表时间: 2023-07-18
• 期刊: CELL REPORTS MEDICINE
• 影响因子: 14.3
• 作者: Lentini, Germana;Fama, Agata;De Gaetano, Giuseppe Valerio;Coppolino, Francesco;Mahjoub, Ahlem Khachroub;Ryan, Liv;Lien, Egil;Espevik, Terje;Beninati, Concetta;Teti, Giuseppe
• 通讯作者: Teti, Giuseppe

MLKL-Driven Inflammasome Activation and Caspase-8 Mediate Inflammatory Cell Death in Influenza A Virus Infection.

• DOI: 10.1128/mbio.00110-23
• 发表时间: 2023-04-25
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Lei, Xuqiu;Chen, Yongzhi;Lien, Egil;Fitzgerald, Katherine A.
• 通讯作者: Fitzgerald, Katherine A.