Structural studies of gasdermin E and its recognition by caspase-3.

Gasdermin E 的结构研究及其被 caspase-3 识别。

基本信息

  • 批准号:
    10571048
  • 负责人:
  • 金额:
    $ 8.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-11-03 至 2024-10-31
  • 项目状态:
    已结题

项目摘要

Abstract The canonical and noncanonical inflammasome signaling pathways can induce pyroptosis and secretion of inflammatory cytokines, which function as crucial immune defense mechanisms in microbial killing and clearance. Pyroptosis is a type of regulated lytic cell death that is mediated by members of the gasdermin family that assemble membrane pores upon cleavage by proteases. Gasdermin E (GSDME) can be cleaved by apoptotic caspases-3 and 7, which then triggers plasma membrane pore formation and pyroptosis instead of apoptosis. GSDME-mediated pyroptosis and cytokine release play crucial roles in host defense against viral or bacterial infections. On the other hand, GSDME in intestinal epithelial cells has been implicated in mucosal inflammation and pathogenesis of Crohn’s disease, and GSDME-mediated pyroptosis contributes to renal fibrosis and kidney injury. Despite recent progress in our understanding of the recruitment and recognition of gasdermin D (GSDMD) by inflammatory caspases, the molecular mechanisms of GSDME recognition and cleavage by apoptotic caspases have been poorly defined. This proposal aims to address the critical gaps in our knowledge using complementary structure-function approaches. We hypothesize that inactive GSDME is maintained in an autoinhibited conformation through intramolecular amino-terminal domain (NTD)-carboxy- terminal domain (CTD) interactions, which is recognized by apoptotic caspase-3 that cleaves at the NTD-CTD linker region to release the autoinhibition. This study will explore the structural mechanisms of GSDME autoinhibition and its recognition by caspase-3 to test the above hypothesis. The following specific aims are built on our past and ongoing studies on gasdermins and pyroptosis. Aim 1 will characterize the molecular mechanisms of GSDME autoinhibition. Our preliminary data show that GSDME protein can be crystallized and the crystals diffracted X-ray well. We will determine the structure of GSDME at its autoinhibitory state using crystallographic approaches, and validate the NTD-CTD interface through mutagenesis studies of the interface residues using LDH release, PI uptake, and liposome leakage assays. Aim 2 will define the mechanisms of GSDME recognition by caspase-3. We will probe the interaction between GSDME and caspase-3 through biochemical and cell biology techniques, and determine the structure of GSDME in complex with caspase-3 using X-ray crystallography. The success of this proposal will not only reveal important insights into GSDME autoinhibition and recognition by apoptotic caspases that move the field forward, but also facilitate the development of specific inhibitors for apoptotic caspase-3 based on the distinct GSDME-caspase-3 interface, which may be valuable reagents in the study of both pyroptosis and apoptosis signaling pathways.
摘要 典型的和非典型的炎症体信号通路可以诱导下垂和分泌 炎性细胞因子,在微生物死亡和死亡中发挥关键免疫防御机制 通行证。下睑下垂是一种由Gasdermin家族成员介导的调节性溶解细胞死亡 在被蛋白水解酶切割时组装膜孔。Gasdermin E(GSDME)可被 凋亡的caspase-3和7,然后触发质膜孔洞形成和下垂,而不是 细胞凋亡。GSDME介导的上睑下垂和细胞因子释放在宿主抵御病毒感染中起着至关重要的作用 细菌感染。另一方面,肠上皮细胞中的GSDME被认为与粘膜有关 克罗恩病的炎症和发病机制及GSDME介导的肾炎性下垂 纤维化和肾脏损伤。尽管我们最近在了解招募和承认 炎症性caspase对Gasdermin D(GSDMD)的作用,GSDME识别和表达的分子机制 被凋亡的半胱氨酸天冬氨酸酶切割的研究还不是很清楚。这项提议旨在解决我们的关键差距 使用互补的结构-功能方法的知识。我们假设不活跃的GSDME是 通过分子内氨基末端结构域(NTD)-羧基保持自抑制构象- 末端结构域(CTD)相互作用,由在NTD-CTD处裂解的凋亡caspase-3识别 链接器区域来释放自身抑制。本研究将探讨GSDME的结构机制 自身抑制及其被caspase-3识别来验证上述假说。建立了以下具体目标 关于我们过去和正在进行的关于加德明和上睑下垂的研究。目标1将描述分子 GSDME自身抑制的机制。我们的初步数据显示,GSDME蛋白可以结晶并 晶体对X射线有良好的衍射性。我们将确定GSDME在自抑制状态下的结构 结晶学方法,并通过对NTD-CTD界面的诱变研究验证该界面 残留采用乳酸脱氢酶释放、PI摄取和脂质体渗漏分析。目标2将定义以下机制 Caspase-3对GSDME的识别。我们将通过以下途径探讨GSDME与caspase-3的相互作用 生化和细胞生物学技术,并确定GSDME与caspase-3的复合体的结构 使用X射线结晶学。这一提议的成功不仅将揭示对GSDME的重要见解 自我抑制和被凋亡的半胱氨酸酶识别,不仅推动了这个领域的发展,而且也促进了 基于不同的GSDME-caspase-3界面的凋亡特异性caspase-3抑制剂的开发 它们可能是研究上睑下垂和细胞凋亡信号通路的有价值的试剂。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Tsan Sam Xiao其他文献

132 : Sensing of DNA by innate immune receptors
  • DOI:
    10.1016/j.cyto.2013.06.135
  • 发表时间:
    2013-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Tengchuan Jin;Jiansheng Jiang;Patrick Smith;Tsan Sam Xiao
  • 通讯作者:
    Tsan Sam Xiao

Tsan Sam Xiao的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Tsan Sam Xiao', 18)}}的其他基金

Molecular mechanisms of gasdermin recognition by proteases and autophagy proteins in cytokine release
细胞因子释放中蛋白酶和自噬蛋白识别gasdermin的分子机制
  • 批准号:
    10654580
  • 财政年份:
    2020
  • 资助金额:
    $ 8.05万
  • 项目类别:
Molecular mechanisms of gasdermin recognition by proteases and autophagy proteins in cytokine release
细胞因子释放中蛋白酶和自噬蛋白识别gasdermin的分子机制
  • 批准号:
    10024454
  • 财政年份:
    2020
  • 资助金额:
    $ 8.05万
  • 项目类别:
Molecular mechanisms of gasdermin recognition by proteases and autophagy proteins in cytokine release
细胞因子释放中蛋白酶和自噬蛋白识别gasdermin的分子机制
  • 批准号:
    10441356
  • 财政年份:
    2020
  • 资助金额:
    $ 8.05万
  • 项目类别:
Molecular mechanisms of gasdermin recognition by proteases and autophagy proteins in cytokine release
细胞因子释放中蛋白酶和自噬蛋白识别gasdermin的分子机制
  • 批准号:
    10223159
  • 财政年份:
    2020
  • 资助金额:
    $ 8.05万
  • 项目类别:
Mechanisms of tunable posttranslational control of T-cell homeostasis and tolerance
T 细胞稳态和耐受性的可调节翻译后控制机制
  • 批准号:
    10410503
  • 财政年份:
    2019
  • 资助金额:
    $ 8.05万
  • 项目类别:
Mechanisms of tunable posttranslational control of T-cell homeostasis and tolerance
T 细胞稳态和耐受性的可调节翻译后控制机制
  • 批准号:
    10631929
  • 财政年份:
    2019
  • 资助金额:
    $ 8.05万
  • 项目类别:
Molecular mechanisms of gasdermins and pyroptosis
Gasdermin 和细胞焦亡的分子机制
  • 批准号:
    10112920
  • 财政年份:
    2018
  • 资助金额:
    $ 8.05万
  • 项目类别:
Developing chemical probes that target specific inflammasomes
开发针对特定炎症体的化学探针
  • 批准号:
    9101571
  • 财政年份:
    2016
  • 资助金额:
    $ 8.05万
  • 项目类别:

相似海外基金

How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
  • 批准号:
    2315783
  • 财政年份:
    2023
  • 资助金额:
    $ 8.05万
  • 项目类别:
    Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
  • 批准号:
    2719534
  • 财政年份:
    2022
  • 资助金额:
    $ 8.05万
  • 项目类别:
    Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
  • 批准号:
    20K01113
  • 财政年份:
    2020
  • 资助金额:
    $ 8.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2633211
  • 财政年份:
    2020
  • 资助金额:
    $ 8.05万
  • 项目类别:
    Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2436895
  • 财政年份:
    2020
  • 资助金额:
    $ 8.05万
  • 项目类别:
    Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2633207
  • 财政年份:
    2020
  • 资助金额:
    $ 8.05万
  • 项目类别:
    Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
  • 批准号:
    19K01745
  • 财政年份:
    2019
  • 资助金额:
    $ 8.05万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
  • 批准号:
    426559561
  • 财政年份:
    2019
  • 资助金额:
    $ 8.05万
  • 项目类别:
    Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
  • 批准号:
    2236701
  • 财政年份:
    2019
  • 资助金额:
    $ 8.05万
  • 项目类别:
    Studentship
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
  • 批准号:
    415543446
  • 财政年份:
    2019
  • 资助金额:
    $ 8.05万
  • 项目类别:
    Research Fellowships
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了