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： 细菌分泌系统效应子对于许多伴有病原体的病毒性至关重要。 效应蛋白阻止了钥匙的免疫信号通路。 原因也可以由先天免疫系统发送。 蛋白质可以被认为是病理和触发免疫反应，这一过程称为作用 - 触发免疫力（ETI）。 机制是宿主和病原体之间的武器竞赛的主要驱动因素 关于该过程对于理解双方病毒性和宿主防御至关重要。 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的成熟IL-1B/IL-18 最近证明是炎性小体的关键介体，触发了通过乳沟在居住D276处触发的凋亡 caspase-1/11，释放的N末端片段在细胞中产生孔隙 膜完整性也与IL-1β和IL-18释放有关。 致病性Yersinia spp。，鼠疫和胃肠炎的病因，触发细胞死亡及IL-1β/IL- 18释放。 激酶和caspase-8通常与凋亡死亡相关，可控制细胞因子释放和 Yelsinia感染后的巨噬细胞毒性。 YopJ强烈地激活了caspase-8，这是无非途径。 与生理学相关的模型系统系统研究了caspase-8在双臂感染中的作用。 特别是，我们的支持数据表明YOPJ对TAK1和IKKβ激酶的抑制会激活caspase-8 并诱导非典型的炎症途径，这不是取决于caspase-1或-11 在使用tak1和Ikk活性时观察到响应，模仿Yopj的作用。 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。 通过RIPK1和CASPASE-8触发新型的Efector介导的免疫反应，导致GSDMD 裂解，细胞死亡和IL-1β释放。 激活GSDMD是此处解决的批判性问题

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.