MECHANISMS OF ACTIVATION OF ICE-LIKE CYSTEINE PROTEASES

冰样半胱氨酸蛋白酶的激活机制

基本信息

批准号：
7672257
负责人：
Emad S Alnemri
金额：
$ 31.67万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-01-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7672257
关键词：
ABL1 gene Adaptor Signaling Protein Affect Aging Anti-Inflammatory Agents Anti-inflammatory Binding Biochemical Biological Boxing Caspase-1 Cell Death Cell Proliferation Cellular Stress Chemicals Chronic Disease Complex Cysteine Protease Cytoskeleton Disease Extracellular Space Familial Mediterranean Fever Fever Human Ice Immune Cell Activation Immune response In Vitro Infection Inflammation Inflammation Mediators Inflammatory Interleukin-12 Interleukin-18 Laboratories Lead Ligation Maps Mediating Membrane Proteins Mitochondria Molecular Mutate PAPA syndrome PTPN12 gene Pathway interactions Phosphorylation Play Process Production Proline Protein Serine/Threonine Phosphatase Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Proteolysis Proteomics RNA Interference Regulation Research Role SH3 Domains Signal Transduction Stress Structure TLR2 gene TLR4 gene Therapeutic Tyrosine c-abl Proto-Oncogenes cytokine cytosolic receptor design high throughput screening inhibitor/antagonist interleukin-18 receptor macrophage marenostrin novel public health relevance response small molecule

项目摘要

DESCRIPTION (provided by applicant): Caspase-1 is an important component of the innate immune response against pathogenic infection and cellular stresses. Activation of caspase-1 can lead to processing of the inactive pro-IL-12 and pro-IL-18 to produce the active cytokines IL-12 and IL-18, respectively, which are potent mediators of inflammation that stimulate fever, recruitment and activation of immune cells, production of secondary cytokines and cellular proliferation. Caspase-1 activation can also lead to an inflammatory form of cell death called pyroptosis. The applicant's laboratory demonstrated recently that this form of cell death is mediated by the caspase-1 adaptor protein ASC, which assembles a supramolecular structure termed the pyroptosome that activates caspase-1 during pyroptosis in response to diverse pro-inflammatory and stress signals. They have also elucidated the role of pyrin, a protein mutated in familial Mediterranean fever, in caspase-1 activation and inflammation in the human auto-inflammatory PAPA syndrome, and demonstrated that pyrin is a homotrimeric cytosolic receptor for the cytoskeleton- organizing protein PSTPIP1. Ligation by PSTPIP1 activates pyrin by unmasking of its PYD domain, which then interacts with ASC and facilitates ASC oligomerization into the active pyroptosome. In this application specific aims are proposed to extend these ongoing studies to further investigate the regulation and molecular determinants of the interaction between PSTPIP1 and pyrin. In particular, the aims will focus on characterizing the exact role of the protein-tyrosine phosphatase PTP-PEST and tyrosine kinase c-Abl, both of which have been shown to interact with PSTPIP1, in the pyrin-mediated caspase-1 activation pathway. It is also proposed to characterize novel upstream activators of the ASC pyroptosome and further investigate the role TLR2, TLR4, cryopyrin and caspase-1-mediated proteolysis in macrophage pyroptosis. Finally, studies are proposed to investigate the potential use of the in vitro ASC pyroptosome assembly as a high throughput screen to identify small molecule therapeutics to inhibit and treat inflammation. PUBLIC HEALTH RELEVANCE: Inflammation is a key process in the innate immune response to infections and cellular stress. This research focuses on understanding the role of key cellular proteins in the complex molecular and cellular inflammatory mechanisms. The results of this research will help in the design and discovery of effective therapeutics to treat inflammation associated with aging, auto-inflammatory disease and chronic inflammatory diseases.

描述（由申请人提供）：caspase-1是针对致病感染和细胞应激的先天免疫反应的重要组成部分。 caspase-1的激活可以导致无效的Pro-IL-12和Pro-IL-18分别产生活性细胞因子IL-12和IL-18，它们是刺激发烧，募集和激活免疫细胞的炎症的有效介体，产生了二次细胞因子和细胞增生。 caspase-1激活还会导致一种称为流胞病的细胞死亡的炎症形式。申请人的实验室最近证明，这种形式的细胞死亡是由caspase-1适配器蛋白ASC介导的，caspase-1适配器蛋白ASC组装了一种被称为闪光体的超分子结构，该结构被称为圆锥体，该结构在响应多样的炎性炎性和应激信号的响应中激活了caspase-1。他们还阐明了吡啶的作用，一种在家族性地中海发烧中突变的蛋白质，在人自发炎症爸爸综合征中的caspase-1激活和炎症中的作用，并证明了吡啶是细胞骨架 - 有组织蛋白PSTPIP1的同型二聚体细胞质受体。 PSTPIP1的连接通过揭露其PYD结构域激活吡啶，然后与ASC相互作用并促进ASC寡聚成活跃的圆锥体。在此应用程序中，提出了特定的目的，以扩展这些正在进行的研究，以进一步研究PSTPIP1和Pyrin之间相互作用的调节和分子决定因素。特别是，该目标将集中于表征蛋白酪氨酸磷酸酶PTP-PEST和酪氨酸激酶C-ABL的确切作用，这些蛋白质磷酸酶PTP-PEST和酪氨酸激酶C-ABL在Pyrin介导的caspase-1激活途径中均显示与PSTPIP1相互作用。还提出了表征ASC旋转体的新型上游活化剂，并进一步研究了巨噬细胞增生中的TLR2，TLR4，冷冻蛋白和caspase-1介导的蛋白水解的作用。最后，提出了研究来研究体外ASC旋食体组装作为高吞吐量筛查的潜在使用，以鉴定小分子疗法以抑制和治疗炎症。公共卫生相关性：炎症是对感染和细胞压力的先天免疫反应的关键过程。这项研究重点是了解关键细胞蛋白在复杂分子和细胞炎症机制中的作用。这项研究的结果将有助于设计和发现有效的治疗剂，以治疗与衰老，自发疾病和慢性炎症性疾病有关的炎症。