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

Gasdermins（GSDM）代表引起该领域注意的相关蛋白质家族 最近有一个有趣的生物学。GSDM家族在人类中包括六个成员（GSDMA， GSMDB、GSDMC、GSDMD、GSDME/DFNA 5和DFNB 59），并且在小鼠中， GSDMA1-3最近，GSDMD被鉴定为炎性小体的下游效应物， 其是激活炎性半胱天冬酶（人中为-1、-4和-5， 1和-11在小鼠中）。GSDMD被半胱天冬酶切割以产生N-末端片段（GSDMD-1）。 NT）和C-末端片段（GSDMD-CT）。GSDMD-NT介导细胞凋亡，一种裂解性细胞死亡 包括细胞内容物的溢出，以及IL-1β细胞因子的分泌，其通过 caspase-1的成熟形式。 我们和其他人发现，在被炎性半胱天冬酶切割后，GSDMD-NT特异性结合于 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上形成孔而在哺乳动物细胞中表现出强的膜破坏细胞毒性。 在细胞凋亡和体外的膜。其他GSDM对炎性半胱天冬酶不敏感。 GSDME（也称为DFNA 5）被细胞凋亡半胱天冬酶（-3和-7）激活， 还通过在与炎性半胱天冬酶不同的位点切割GSDMD来特异性阻断焦亡 来消化蛋白质。与凋亡半胱天冬酶类似，肠道病毒71（EV 71）病毒蛋白酶3C切割 GSDMD在一个独特的网站，以阻止它，并抑制病毒诱导的焦亡。活化酶 剩下的GSDM还有待发现 重要的是，GSDM在各种组织中表达，似乎表现出通用的孔， 形成活性，表明它们各自在不同的生理条件下介导裂解性细胞死亡。 和病理学背景。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提供了对gasdermin介导的细胞死亡的新认识 焦亡，而且还提供了新的治疗策略，用于治疗炎性小体相关， gasdermin相关疾病

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.