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：
10171760
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/10171760
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 Cleaved cell 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.

Gasdermin (GSDM) 代表了引起该领域关注的相关蛋白家族最近，GSDM 家族由六个人类成员组成（GSDMA、 GSMDB、GSDMC、GSDMD、GSDME/DFNA5 和 DFNB59），在小鼠中，GSDMA 的三种形式是目前，GSDMA1-3 最近被确定为炎症小体的下游效应子，它们是激活炎症半胱天冬酶的超分子复合物（在人类中为 -1、-4 和 -5，并且 - 小鼠中的 GSDMD 为 1 和 -11）。 NT) 和 C 末端片段 (GSDMD-CT) 介导焦亡，一种裂解性细胞死亡。细胞内容物的溢出以及 IL-1β 细胞因子的分泌，其中涉及由 caspase-1 至成熟形式。我们和其他人发现，在被炎症性半胱天冬酶裂解后，GSDMD-NT 特异性结合磷脂酰肌醇磷酸（PIP）、磷脂酸（PA）、磷脂酰丝氨酸（PS）和心磷脂，并通过在哺乳动物细胞中形成孔而表现出强烈的膜破坏细胞毒性其他 GSDM 在细胞焦亡过程中和体外对炎性半胱天冬酶不敏感。 GSDME（也称为 DFNA5）被证明可被凋亡半胱天冬酶（-3 和 -7）激活，这还通过在与炎症半胱天冬酶不同的位点裂解 GSDMD 来特异性阻止细胞焦亡与凋亡半胱天冬酶类似，肠道病毒 71 (EV71) 病毒蛋白酶 3C 会裂解该蛋白质。 GSDMD 在特定位点使其失活并抑制病毒诱导的细胞焦亡。其余的 GSDM 仍有待发现。重要的是，在多种组织中表达的 GSDM 似乎表现出通用的孔道体外形成活性，表明它们各自在不同的生理条件下介导裂解细胞死亡在这里，我们建议通过以下方式阐明孔隙形成的结构机制。 GSDM 家族；了解 GSDMD 和其他 Gasdermin 蛋白的调节和发挥作用它们的孔形成活性不仅将为gasdermin介导的细胞死亡提供新的见解，包括细胞焦亡，而且还为治疗炎症体相关和与gasdermin相关的疾病。