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Elucidating the structural mechanism of pore formation by the (GSDM) Gasdermin family

阐明 (GSDM) Gasdermin 家族孔隙形成的结构机制

基本信息

批准号：
10417119
负责人：
Hao Wu
金额：
$ 51.45万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-12 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417119
关键词：
3-Dimensional Acids Alopecia Alzheimer&apos s Disease Apoptotic Architecture Asthma Attention Binding Biochemical Biological Biological Assay Biological Process Biology C-terminal CASP1 gene CASP3 gene Cardiolipins Cardiovascular Diseases Caspase Cell Death Cellular Assay Chemicals Complex Cryoelectron Microscopy Crystallization Cytolysins DNA Sequence Alteration Data Data Collection Disease Dissection Enterovirus 71 Enzymes Exhibits Extravasation Family Family member Genetic Diseases Genetic Polymorphism Human Hyperkeratosis Immunology In Vitro Inflammasome Inflammatory Interleukin-1 beta Link Lipid Binding Lipids Liposomes Lytic Malignant Neoplasms Mammalian Cell Mediating Membrane Metabolic Diseases Molecular Conformation Mus Mutation N-terminal Paper Pathologic Pathway interactions Peptide Hydrolases Phosphatidic Acid Phosphatidylinositol Phosphates Phosphatidylserines Physiological Play Process Proteins Regulation Resolution Risk Role Sepsis Series Site Structure System Therapeutic Tissues Validation Viral Virus base cytokine cytotoxicity data structure design fascinate grasp hearing impairment human disease improved in vitro activity insight member mutant novel therapeutic intervention reconstitution screening small molecule

项目摘要

Gasdermins (GSDMs) represent a family of related proteins that caught the attention of the field recently with fascinating biology. The GSDM family comprises six members in human (GSDMA, GSMDB, GSDMC, GSDMD, GSDME/DFNA5, and DFNB59), and in mouse, three forms of GSDMA are present, GSDMA1-3. Recently, GSDMD was identified as a downstream effector of inflammasomes, which are supramolecular complexes that activate inflammatory caspases (-1, -4 and -5 in human and - 1 and -11 in mouse). GSDMD gets cleaved by caspases to generate an N-terminal fragment (GSDMD- NT) and a C-terminal fragment (GSDMD-CT). GSDMD-NT mediates pyroptosis, a lytic cell death involving spillage of cellular contents, as well as secretion of the IL-1β cytokine, which is processed by caspase-1 to the mature form. We and others found that upon cleavage by inflammatory caspases, GSDMD-NT specifically binds to phosphatidylinositol phosphates (PIPs), phosphatidic acid (PA), phosphatidylserine (PS) and cardiolipin, and exhibits strong membrane-disrupting cytotoxicity in mammalian cells by forming pores on membranes during pyroptosis and in vitro. Other GSDMs are insensitive to inflammatory caspases. GSDME (also known as DFNA5) was shown to be activated by apoptotic caspases (-3 and -7), which also specifically block pyroptosis by cleaving GSDMD at a distinct site from the inflammatory caspases to inactivate the protein. Similar to apoptotic caspases, Enterovirus 71 (EV71) viral protease 3C cleaves GSDMD at a distinct site to inactivate it and to inhibit virus-induced pyroptosis. The activating enzymes for the remaining GSDMs remain to be discovered. Importantly, GSDMs, which are expressed in a variety of tissues, appear to exhibit a universal pore formation activity in vitro, suggesting that they each mediate lytic cell death under different physiological and pathological contexts. Here we propose to elucidate the structural mechanism of pore formation by the GSDM family; understanding how GSDMD and other gasdermin proteins are regulated and exert their pore forming activity will not only provide new insights on gasdermin-mediated cell death including pyroptosis, but also afford new therapeutic strategies for treating inflammasome-related and gasdermin-related diseases.

Gasdermins(GSDM)代表了一个引起该领域关注的相关蛋白质家族最近研究了令人着迷的生物学。GSDM家族包括人类的六个成员(GSDMA， GSMDB、GSDMC、GSDMD、GSDME/DFNA5和DFNB59)，在小鼠体内，GSDMA的三种形式是目前，GSDMA1-3。最近，GSDMD被确定为炎性小体的下游效应因子，它们是激活炎症caspase(-1、-4和-5)的超分子复合体，在人和- 1和-11)。GSDMD被半胱氨酸酶切割，产生N-末端片段(GSDMD- NT)和一个C-末端片段(GSDMD-CT)。GSDMD-NT介导的溶血性细胞死亡--上睑下垂涉及细胞内容物的溢出以及IL-1β细胞因子的分泌，后者由 Caspase-1转化为成熟型。我们和其他人发现，当被炎性半胱氨酸酶切割时，GSDMD-NT特异性地结合到磷脂酰肌醇磷酸盐(PIPs)、磷脂酸(PA)、磷脂酰丝氨酸(PS)和心磷脂，在哺乳动物细胞中表现出很强的膜破坏细胞毒性，因为它在上睑下垂时的膜和体外的膜。其他GSDM对炎性caspase不敏感。 GSDME(也被称为DFNA5)被证明是由凋亡的caspase(-3和-7)激活的，它还通过在与炎性半胱氨酸酶不同的位置切割GSDMD来特异性地阻断下垂使蛋白质失活。与凋亡的caspase类似，肠道病毒71(EV71)病毒蛋白水解酶3C被裂解 GSDMD在一个不同的位置灭活它，并抑制病毒诱导的下垂。活化酶至于其余的GSDM，则有待发现。重要的是，在各种组织中表达的GSDM似乎表现出普遍的毛孔体外形成活性，提示它们各自在不同的生理条件下介导溶细胞死亡。以及病态的背景。在这里，我们建议阐明孔隙形成的结构机制 GSDM家族；了解GSDMD和其他Gasdermin蛋白是如何调节和发挥作用的它们的成孔活性不仅将为Gasdermin介导的细胞死亡提供新的见解，包括但也为治疗炎症性和炎症性下垂提供了新的治疗策略与Gasdermin相关的疾病。