GSDMD-dependent IL-1 signaling in intestinal inflammation

肠道炎症中 GSDMD 依赖性 IL-1 信号传导

基本信息

  • 批准号:
    10223160
  • 负责人:
  • 金额:
    $ 54.17万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-24 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Abstract: About 1.3 million people suffer from IBD (chronic inflammation of the intestine) in the United States. The etiology of IBD remains elusive and preventive measures or a cure are not available. Inflammasomes and derived cytokines IL-1β are being intensely investigated as the signaling hub that is dys-regulated in inflammatory bowel disease (IBD). IL-1β is synthesized as inactive pro-forms with no secretory signal sequence. Recent studies have found that a lipid binding protein, Gasdermin D (GSDMD), is required for release of IL-1β in response to caspase-1/11 inflammasome activation. This breakthrough led to a rapid growth of literature that focuses on the pore forming and associated pyroptotic activity of GSDMD in myeloid cells. Interestingly, we discovered a novel nonpyrototic role of GSDMD in guiding the release of IL-1β containing vesicles from intestinal epithelia cells and T cells in response to Caspase 8 (Casp8) but not casp1 activation. Through unbiased proteomic analysis, we identified a set of novel GSDMD-interacting proteins in intestinal epithelial cells (IECs), including NEDD4 (an E3 ligase) and the Hsp90 co-chaperone CDC37. Ablation of GSDMD or NEDD4 abolished LPS and ATP-induced IL-1β production from IECs. Strikingly, LPS+ATP stimulation led to the polyubiquitination of pro-IL-1β, which was secreted and processed into mature IL-1β along with a complex containing full-length GSDMD, Hsp90/CDC37, NEDD4, Atg7, Casp8 but not Casp1. In vitro ubiquitination assay demonstrated that NEDD4, known to interact with LC3 and promote cargo loading into secretory vesicles, catalyzed the polyubiquitination of pro-IL-1β. Indeed, while GSDMD was associated with LC3+ vesicles; GSDMD-dependent release of extracellular vesicles (< 200 nm) were detected by electron microscopy, which contains the GSDMD/NEDD4/IL-1β complex. Moreover, inactivating mutation in the Asp276 of GSDMD, which abolishes its pore-forming and pyroptotic activity, did not impact the GSDMD-guided IL-1β secretion from IECs. In TH17 cells, a T helper cell subset highly relevant to intestinal inflammation, this GSDMD-guided secretion of polyubiquitinated pro-IL-1β complex (GSDMD, Hsp90, Casp8 and NEDD4) was also readily detected in response to ATP stimulation and TCR activation. Collectively, the data revealed a novel nonpyroptotic role for GSDMD in IL-1β release from non-myeloid cells. The pathogenic role of the GSDMD-guided IL-1β release was investigated in two mouse models of intestinal inflammation. Firstly, while polyubiquitinated pro-IL-1β, mIL-1β and the GSDMD/NEDD4-secretary complex were induced in a GSDMD-dependent manner in the intestinal explants in response to dextran sodium sulfate (DSS)-induce colitis, GSDMD-deficiency attenuated the intestinal inflammation. Secondly, GSDMD or IL-1β deficiency in naïve T cells reduced their ability to elicit intestinal inflammation. Based on these findings, we hypothesize that the GSDMD mediates distinct pathways (guided secretion and pyroptosis) for IL-1β release in non-myeloid and myeloid cells, which jointly contribute to the pathogenesis of intestinal inflammation in a coordinated manner. We will test this hypothesis through the following aims: (1) Investigate the molecular mechanism for GSDMD-guided secretory pathway for IL-1β release; (2) Investigate the cell-type and pathway-specific role of GSDMD-IL-1β axis in intestinal inflammation, including GSDMD-mediated pyroptotic versus GSDMD-guided IL-1β secretion on the intestinal inflammation.
摘要: 在美国,大约有130万人患有IBD(慢性肠炎)。病因学 IBD的发病率仍然难以捉摸,也没有预防措施或治愈方法。炎性小体及其衍生 细胞因子IL-1β作为炎症性肠病中异常调节的信号中枢正被广泛研究 疾病(IBD)。IL-1β是以无分泌信号序列的非活性前体形式合成的。最新研究 发现一种脂质结合蛋白GasderminD(GSDMD)是释放IL-1β所必需的 Caspase-1/11炎症体激活。这一突破导致了以文学为中心的文学的迅速发展 GSDMD在髓系细胞中的孔道形成和相关的嗜热活性。有趣的是,我们发现了一本小说 GSDMD在引导肠上皮细胞释放含有IL-1β的囊泡中的非解热作用 T细胞对Caspase 8(Caspase8)的反应,但对CASP1的激活无反应。通过无偏见的蛋白质组分析,我们 在肠上皮细胞中发现了一组新的GSDMD相互作用蛋白,包括NEDD4(一个E3 连接酶)和Hsp90辅助伴侣CDC37。消融GSDMD或NEDD4可消除内毒素和三磷酸腺苷诱导的 IECS生产IL-1β。值得注意的是,内毒素+三磷酸腺苷刺激导致前-IL-1β的多泛素化,这是 分泌并加工成成熟的IL-1β以及含有全长GSDMD、Hsp90/CDC37、 NEDD4、ATG7、Casp8,但不包括CASP1。体外泛素化实验表明,已知相互作用的NEDD4 与Lc3结合,促进货物装入分泌囊泡,催化前IL-1β的多泛素化。的确, 而GSDMD与Lc3+囊泡有关;依赖GSDMD的胞外囊泡释放(&lt;200 NM),其中含有GSDMD/NEDD4/IL-1β复合体。此外, GSDMD的Asp276的失活突变,取消了其成孔和焦链活性,但没有 影响GSDMD诱导的IECs分泌IL-1β。在TH17细胞中,高度相关的辅助性T细胞亚群 肠道炎症,这种由GSDMD引导的多泛素化前IL-1β复合体(GSDMD,Hsp90, Casp8和NEDD4)也很容易在ATP刺激和TCR激活时检测到。总而言之, 这些数据揭示了GSDMD在非髓系细胞释放IL-1β中的一种新的非嗜热性作用。致病的 在两种小鼠肠道炎症模型中,研究了GSDMD引导的IL-1β释放的作用。首先, 而多泛素化的前IL-1β、mIL-1β和GSDMD/NEDD4-分泌复合体在 葡聚糖硫酸钠(DSS)诱导的结肠炎时肠道组织中GSDMD依赖的方式, GSDMD缺乏可减轻肠道炎症。第二,幼稚T细胞GSDMD或IL-1β缺乏 降低了它们引发肠道炎症的能力。基于这些发现,我们假设GSDMD 介导非髓系细胞和髓系细胞释放IL-1β的不同途径(引导分泌和下垂), 它们共同作用于肠道炎症的发病机制。我们将对此进行测试 通过以下目的提出假说:(1)探讨GSDMD诱导分泌的分子机制 IL-1β释放途径;(2)探讨GSDMD-IL-1β轴的细胞类型和途径特异性作用。 肠道炎症,包括GSDMD介导的嗜热性与GSDMD引导的IL-1β的分泌 肠道发炎。

项目成果

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Theresa Torres Pizarro其他文献

Theresa Torres Pizarro的其他文献

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{{ truncateString('Theresa Torres Pizarro', 18)}}的其他基金

The pathogenic roles of GSDMD-dependent gut epithelium extracellular vesicles in IBD
GSDMD依赖性肠上皮细胞外囊泡在IBD中的致病作用
  • 批准号:
    10853519
  • 财政年份:
    2023
  • 资助金额:
    $ 54.17万
  • 项目类别:
The pathogenic roles of GSDMD-dependent gut epithelium extracellular vesicles in IBD
GSDMD依赖性肠上皮细胞外囊泡在IBD中的致病作用
  • 批准号:
    10386894
  • 财政年份:
    2021
  • 资助金额:
    $ 54.17万
  • 项目类别:
The pathogenic roles of GSDMD-dependent gut epithelium extracellular vesicles in IBD
GSDMD依赖性肠上皮细胞外囊泡在IBD中的致病作用
  • 批准号:
    10599251
  • 财政年份:
    2021
  • 资助金额:
    $ 54.17万
  • 项目类别:
The pathogenic roles of GSDMD-dependent gut epithelium extracellular vesicles in IBD
GSDMD依赖性肠上皮细胞外囊泡在IBD中的致病作用
  • 批准号:
    10211603
  • 财政年份:
    2021
  • 资助金额:
    $ 54.17万
  • 项目类别:
GSDMD-dependent IL-1 signaling in intestinal inflammation
肠道炎症中 GSDMD 依赖性 IL-1 信号传导
  • 批准号:
    10654589
  • 财政年份:
    2020
  • 资助金额:
    $ 54.17万
  • 项目类别:
GSDMD-dependent IL-1 signaling in intestinal inflammation
肠道炎症中 GSDMD 依赖性 IL-1 信号传导
  • 批准号:
    10441357
  • 财政年份:
    2020
  • 资助金额:
    $ 54.17万
  • 项目类别:
Histology/Imaging Core C
组织学/成像核心 C
  • 批准号:
    10555242
  • 财政年份:
    2015
  • 资助金额:
    $ 54.17万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    10555238
  • 财政年份:
    2015
  • 资助金额:
    $ 54.17万
  • 项目类别:
Histology/Imaging Core C
组织学/成像核心 C
  • 批准号:
    10361545
  • 财政年份:
    2015
  • 资助金额:
    $ 54.17万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    10361543
  • 财政年份:
    2015
  • 资助金额:
    $ 54.17万
  • 项目类别:

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