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: 10392961
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392961
• 关键词: Address; Apoptotic; Automobile Driving; Bacteria; Bacterial Infections; Biological Models; CASP1 gene; CASP8 gene; CRISPR screen; Cell Death; Cell Maturation; Cell membrane; Cessation of life; Complex; Data; Defense Mechanisms; Event; Exposure to; Gastroenteritis; Host Defense; Immune response; Immune signaling; Immunity; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Interleukin-1 beta; Interleukin-18; Knowledge; Lead; Link; MAP3K7 gene; Mediating; Mediator of activation protein; 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; design; experimental study; in vivo; innate immune sensing; macrophage; 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

项目概要/摘要： 细菌分泌系统效应子对于许多细菌病原体的毒力至关重要，并且许多 效应蛋白阻断关键的免疫信号通路。然而，这些效应器或它们的改变 先天免疫系统也可以感知原因。例如，效应子介导的宿主修饰 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子 触发免疫（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 这种机制是宿主与病原体之间持续军备竞赛的主要驱动因素。知识 了解这些过程对于了解细菌毒力和宿主防御至关重要。 传统的炎症小体是控制 caspase-1 和/或 11 介导的多分子复合物 焦亡细胞死亡和炎症细胞因子 IL-1b/IL-18 的成熟。 Gasdermin D (GSDMD) 是 最近被证明是炎症小体通过残基 D276 裂解引发细胞焦亡的关键介质 caspase-1/11，释放的 N 末端片段在细胞膜上形成一个孔，从而损害 膜完整性。这些孔还与 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，可引发细胞死亡以及 IL-1β/IL- 18 发布。我们之前描述了一种新颖的非常规炎症小体途径，需要 RIP1 激酶和 caspase-8，通常与细胞凋亡相关，控制细胞因子的释放和 耶尔森菌感染后巨噬细胞的细胞毒性。具体来说，III 型分泌系统 (T3SS) 效应子 YopJ 强烈激活 caspase-8 并驱动这一非常规途径。因此，耶尔森氏菌是一种极好的 生理相关模型系统，用于研究 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 并诱导不依赖于 caspase-1 或 -11 的非经典炎症体途径。相似的 当抑制 TAK1 和 IKK 活性时，会观察到反应，模仿 YopJ 的作用。我们证明 GSDMD 在 D276 处裂解并被耶尔森氏菌以 caspase-8 依赖性方式激活，并且 GSDMD 强烈 调节细胞死亡和 IL-1β/IL-18 释放。这些发现使我们推测耶尔森氏菌 YopJ 通过 RIPK1 和 caspase-8 触发新型效应器介导的免疫反应，从而导致 GSDMD 裂解、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发生的 激活 GSDMD 是本文解决的关键问题