Inflammasome and Gasdermin Signaling Networks for Regulation of Pyroptosis and Cytokine Release

用于调节焦亡和细胞因子释放的炎性体和 Gasdermin 信号网络

基本信息

批准号：
10654563
负责人：
GEORGE R DUBYAK
金额：
$ 188.67万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10654563
关键词：
Acute Alzheimer&apos s Disease Amyloid Apoptosis Apoptotic Autophagocytosis Biochemical Biochemistry CASP1 gene CASP3 gene CASP8 gene CASP9 gene Caspase Categories Cell Death Cell Lineage Cell membrane Cell physiology Cells Cellular biology Chaperone Protein Interaction Chronic Compensation Complex Crohn&apos s disease Cytolysis DNA Disease Disease model Dissociation Dysmyelopoietic Syndromes Effector Cell Elements Epithelial Cells Extracellular Space Familial Mediterranean Fever Functional disorder Genetic Goals Golgi Apparatus Immune Immune response Immunologics Infection Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Innate Immune Response Interleukin-1 beta Investigation Link Literature Lytic Macrophage Mediating Mediator Membrane Molecular Multiple Sclerosis Mus Myeloid Cells Myocardial Infarction N-terminal Necrosis Nonlytic Pathogenesis Pathogenicity Pathway interactions Peptide Hydrolases Peptide Signal Sequences Population Production Proteins Publishing Reagent Regulation Reporting Secretory Vesicles Signal Transduction Source Sterility Stimulus T-Lymphocyte Testing Tissues Ulcerative Colitis VDAC1 gene cell killing cell type cytokine extracellular gastrointestinal granulocyte gut inflammation human disease intestinal epithelium microbial mouse model neutrophil novel programs response restraint structural biology structural determinants trafficking

项目摘要

OVERALL PROGRAM PROJECT: ABSTRACT Cell death pathways have historically been characterized by the proteases that become activated during cell fate decisions. Apoptosis has been defined by initiator and effector caspase activation and, largely due to the reagents available; cell death decisions were initially thought to be binary – caspase-dependent (apoptosis) or caspase-independent (all others). Much like other binary distinctions – like Th1 versus Th2 T cells or M1 versus M2 macrophages, which have undergone substantial expansion in the past decade, cell death decisions and their consequences are now recognized to be much more variables. In fact, even the mechanisms of cell death have been refined. They are no longer categorized by the proteases which activate the cascades but rather, by the effector mechanism. Necroptotic cell death is caused by activation of the pore-forming protein, MLKL. Secondary necrosis is caused by activation of the pore-forming protein, DFNA5 (Gasdermin E/GSDME), and pyroptosis is caused by activation of the pore-forming protein, Gasdermin D (GSDMD) This last category of cell death - pyroptosis - is one of the most immunologically important forms of cell death. Not only does pyroptosis kill the cell, but also GSDMD activation allows the release of IL-1β. This cytokine is among the most important in acute and chronic inflammation. Its secretion is implicated in rare genetic inflammatory diseases such as Familial Mediterranean Fever as well as more common diseases such as myocardial infarction, Alzheimer's disease, Crohn's disease and Ulcerative Colitis, Multiple Sclerosis and many others. With the discovery of the inflammasome in 2002 and its subsequent study, it became clear that the amyloid-like activation of these inflammasome complexes drove pro-IL-1β cleavage and IL-1β release from the cell, but also pyroptosis. Missing from this biochemistry, though, was the cell biology underlying IL-1β release. How is IL- 1β recognized by caspases and other proteases? If IL-1β is not released through a secretory ER-Golgi mechanism, how is trafficked out of the cell? How is this release coordinated with pyroptosis and other regulated cell death pathways that are operative in different populations of immune effector cells. This Program Project aims to utilize cell physiology, biochemistry, structural biology, and mouse and human disease models to unravel these important questions.

总体计划项目：摘要在历史上，细胞死亡途径的特征是蛋白酶在细胞脂肪决策过程中激活。凋亡已通过引发剂和效应子caspase定义激活，很大程度上是由于可用的试剂；细胞死亡的决定最初被认为是二进制 - caspase依赖性（凋亡）或caspase无关（所有其他）。很像其他二进制区分 - 例如Th1与Th2 T细胞或M1与M2巨噬细胞的区别，在过去的十年中，经历了大量扩张，细胞死亡决定及其现在，后果被认为是更多的变量。实际上，即使是细胞死亡已被完善。它们不再被激活的蛋白酶分类级联，而是通过效应器机制。死灵细胞死亡是由孔形成蛋白MLKL的激活。继发坏死是由激活引起的孔形成蛋白，dFNA5（Gasdermin e/gsdme）和凋亡是由激活引起的孔形成蛋白，加油蛋白D（GSDMD）的最后一类细胞死亡 - 凋亡 - 是细胞死亡最重要的形式之一。凋亡不仅会杀死细胞，但GSDMD激活允许释放IL-1β。这种细胞因子是最大的在急性和慢性感染中很重要。它的分泌是在稀有遗传中暗示的炎症性疾病，例如家族性地中海发烧以及更常见的疾病例如心肌梗塞，阿尔茨海默氏病，克罗恩病和溃疡性结肠炎，多发性硬化症和许多其他硬化症。随着2002年发现炎症体的发现随后的研究，很明显，这些炎性体的淀粉样蛋白样激活复合物使细胞的Pro-IL-1β裂解和IL-1β从细胞中释放出来，但也从细胞中释放出来。但是，这种生物化学缺少的是IL-1β释放的细胞生物学。 il-如何 1β由胱天蛋白酶和其他蛋白酶识别？如果未通过分泌释放IL-1β Er-Golgi机制，如何被贩运出来？该版本如何与在不同种群中运行的动物凋亡和其他受调节的细胞死亡途径免疫效应细胞。该计划项目旨在利用细胞生理学，生物化学，结构生物学以及小鼠和人类疾病模型，以揭示这些重要问题。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Ras GTPase-activating-like protein IQGAP1 bridges Gasdermin D to the ESCRT system to promote IL-1β release via exosomes.

DOI：
10.15252/embj.2022110780
发表时间：
2023-01-04
期刊：
EMBO JOURNAL
影响因子：
11.4
作者：
Liao, Yun;Chen, Xing;Miller-Little, William;Wang, Han;Willard, Belinda;Bulek, Katarzyna;Zhao, Junjie;Li, Xiaoxia
通讯作者：
Li, Xiaoxia

The synthetic oleanane triterpenoid CDDO-2P-Im binds GRP78/BiP to induce unfolded protein response-mediated apoptosis in myeloma.

DOI：
10.1002/1878-0261.13447
发表时间：
2023-12
期刊：
MOLECULAR ONCOLOGY
影响因子：
6.6
作者：
Luo, George;Aldridge, Kristin;Chen, Toby;Aslot, Vivek;Kim, Byung-Gyu;Han, Eun Hyang;Singh, Neelima;Li, Sai;Xiao, Tsan Sam;Sporn, Michael B.;Letterio, John J.
通讯作者：
Letterio, John J.

Partners with a killer: Metabolic signaling promotes inflammatory cell death.