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： 细菌分泌系统的影响对于许多细菌病原体的病毒至关重要，并且 效应蛋白阻止关键免疫信号通路。但是，这些影响或它们的改变 天生的免疫系统也可以感知原因。例如，效应子介导的主机修改 蛋白质可以被认为是病理和触发免疫反应，这一过程称为效应 - 触发免疫力（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 是宿主和病原体之间恒定武器竞赛的主要驱动因素的机制。知识 这些过程对于了解细菌病毒以及宿主防御至关重要。 常规炎症体是控制caspase-1和/或11介导的多分子络合物 炎性细胞死亡和炎性细胞因子IL-1B/IL-18的成熟。 Gasdermin D（GSDMD）是 最近，被证明是炎性小体的关键介体，触发了通过在Residence d276上的裂解引起的凋亡。 caspase-1/11，释放的N末端片段在细胞膜折衷中产生了毛孔 膜完整性。这些孔也与IL-1β和IL-18释放有关。巨噬细胞感染 致病性耶尔森氏菌，瘟疫和胃肠炎的灾难性药物，触发细胞死亡以及IL-1β/IL- 18释放。我们先前已经描述了一种新型的非常规炎性途径，需要RIP1 激酶和caspase-8通常与凋亡死亡相关，可控制细胞因子释放和 耶尔森氏菌感染后的巨噬细胞细胞毒性。具体而言，III型分泌系统（T3SS）效应器 YOPJ强烈激活caspase-8并驱动这种非常规的途径。那是耶尔西尼亚很棒的 生理上相关的模型系统，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IKKβ激酶会激活caspase-8 并诱导非典型炎性体途径，这不取决于caspase-1或-11。相似的 当抑制tak1和ikk活性时，观察到响应，模仿YopJ的作用。我们证明GSDMD 在D276上切割并由Yersinia以caspase-8的方式激活，并且GSDMD强烈 调节细胞死亡和IL-1β/IL-18释放。这些发现使我们假设Yersinia Yopj 通过RIPK1和CASPASE-8触发新型效应介导的免疫响应，导致GSDMD 切割，细胞死亡和IL-1β释放。 RIPK1和caspase-8如何激活以及这些事件如何激活 激活GSDMD是本文解决的关键问题

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.