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

• 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
• 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' 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

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（GSDMS）代表一个引起该领域注意的相关蛋白质家族 最近有迷人的生物学。 GSDM家族包括六名人类成员（GSDMA， GSMDB，GSDMC，GSDMD，GSDME/DFNA5和DFNB59），在鼠标中，GSDMA的三种形式是 现在，GSDMA1-3。最近，GSDMD被确定为炎症的下游效应子， 是激活炎症胱天蛋白酶的超分子复合物（人类和 - 鼠标1和-11）。 GSDMD被caspase裂解以产生N末端片段（GSDMD- NT）和C末端片段（GSDMD-CT）。 GSDMD-NT介导凋亡，裂解细胞死亡 涉及细胞含量的溢出以及IL-1β细胞因子的分泌，这是由 caspase-1至成熟形式。 我们和其他人发现，在通过炎症性胱天蛋白酶裂解后，GSDMD-NT特异性结合 磷脂酰肌醇磷酸盐（PIPS），磷脂酸（PA），磷脂酰丝氨酸（PS）和心氨基脂蛋白，磷脂酰甲酸（PA） 并通过形成在 凋亡和体外过程中的膜。其他GSDM对炎症性胱天蛋白酶不敏感。 GSDME（也称为DFNA5）被证明被凋亡病例（-3和-7）激活，其中 还可以通过在炎症胱天蛋白酶的不同位点上切割GSDMD来特异性地阻断凋亡 使蛋白质失活。与凋亡的胱天蛋白酶类似，肠病毒71（EV71）病毒蛋白酶3C切割 GSDMD在一个独特的位点灭活并抑制病毒诱导的凋亡。活化酶 因为其余的GSDM仍有待发现。 重要的是，在多种组织中表达的GSDM似乎表现出通用孔 体外形成活性，表明它们每个人都介导了不同生理的裂解细胞死亡 和病理环境。在这里，我们建议通过 GSDM家族；了解如何调节和执行GSDMD和其他Gasdermin蛋白 他们的孔形成活动不仅会提供有关Gasdermin介导的细胞死亡的新见解，包括 凋亡，但也提供了用于治疗炎性体相关和的新治疗策略 与加油动物有关的疾病。