Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis.
Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis.
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焦亡是由非选择性gasdermin-D孔驱动的，其形态与MLKL通道介导的坏死性凋亡不同
作者：
坏死性凋亡和焦亡是细胞程序性死亡的两种形式，其共同特征是质膜破裂。在此，我们研究的形态学和机制的pyroptosis相比，坏死。与坏死性凋亡不同，焦亡在质膜破裂之前经历膜起泡并产生凋亡小体样细胞突起（称为焦亡小体）。坏死性凋亡的破裂是爆炸样的，而焦亡则导致细胞扁平化。已知坏死性凋亡的发生由质膜中的混合谱系激酶结构域样（MLKL）寡聚体介导，而gasdermin-D（GSDMD）在其被半胱天冬酶-1或半胱天冬酶-11切割后介导焦亡。我们发现，由半胱天冬酶切割产生的GSDMD的N-末端片段（GSDMD-N）也形成寡聚体并迁移到质膜以杀死细胞。MLKL和GSDMD-N都是亲脂性的，并且这两种蛋白质的N-末端序列对于它们的寡聚化和质膜易位是重要的。与MLKL不同，MLKL在质膜上形成通道，诱导选定离子的流入，使细胞膨胀破裂，GSDMD-N形成非选择性孔，并且不依赖于增加的渗透压来破坏细胞。我们的研究揭示了GSDMD的孔形成活性和MLKL的通道形成活性决定了细胞凋亡和细胞坏死中质膜破裂的不同方式。
Necroptosis and pyroptosis are two forms of programmed cell death with a common feature of plasma membrane rupture. Here we studied the morphology and mechanism of pyroptosis in comparison with necroptosis. Different from necroptosis, pyroptosis undergoes membrane blebbing and produces apoptotic body-like cell protrusions (termed pyroptotic bodies) prior to plasma membrane rupture. The rupture in necroptosis is explosion-like, whereas in pyroptosis it leads to flattening of cells. It is known that the execution of necroptosis is mediated by mixed lineage kinase domain-like (MLKL) oligomers in the plasma membrane, whereas gasdermin-D (GSDMD) mediates pyroptosis after its cleavage by caspase-1 or caspase-11. We show that N-terminal fragment of GSDMD (GSDMD-N) generated by caspase cleavage also forms oligomer and migrates to the plasma membrane to kill cells. Both MLKL and GSDMD-N are lipophilic and the N-terminal sequences of both proteins are important for their oligomerization and plasma membrane translocation. Unlike MLKL which forms channels on the plasma membrane that induces influx of selected ions which osmotically swell the cells to burst, GSDMD-N forms non-selective pores and does not rely on increased osmolarity to disrupt cells. Our study reveals the pore-forming activity of GSDMD and channel-forming activity of MLKL determine different ways of plasma membrane rupture in pyroptosis and necroptosis.
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影响因子：
16
作者：
Quarato G;Guy CS;Grace CR;Llambi F;Nourse A;Rodriguez DA;Wakefield R;Frase S;Moldoveanu T;Green DR
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DOI：
10.1073/pnas.1607769113
发表时间：
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