Gasdermin D pore structure reveals preferential release of mature interleukin-1.
Gasdermin D pore structure reveals preferential release of mature interleukin-1.
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DOI：
10.1038/s41586-021-03478-3
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发表时间：
2021-05
期刊：
影响因子：
64.8
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Xia S;Zhang Z;Magupalli VG;Pablo JL;Dong Y;Vora SM;Wang L;Fu TM;Jacobson MP;Greka A;Lieberman J;Ruan J;Wu H
作为先天免疫系统的细胞器，炎症体激活caspase-1和其他炎性caspase，从而裂解Gasdermin D(GSDMD)。Caspase-1还可以裂解IL-1家族的非活性前体，产生成熟的细胞因子，如IL-1、β和IL-18。裂解的GSDMD形成跨膜孔，使IL-1得以释放，并通过下垂驱动裂解细胞死亡。在这里，我们报道了GSDMD的孔和前孔的冷冻电子显微镜结构。这些结构揭示了这两种状态的不同构象，以及广泛的膜结合元件，包括一个疏水锚和三个带正电的斑块。GSDMD孔道主要带负电荷。相反，IL-1前体具有一个酸性结构域，该结构域可被caspase-1蛋白水解性移除。当被GSDMD孔渗透时，未溶解脂质体释放正电荷和中性物质的速度比类似大小的负电荷脂质体快，并且这些孔比它们的前体更有利于IL-1β和IL-18的通过。与这些发现一致的是，活的巨噬细胞(而不是嗜热性巨噬细胞)在GSDMD穿孔时优先释放成熟的IL-1β。GSDMD酸性残基的突变损害了这一偏好，阻碍了前体在细胞内的保留和成熟细胞因子的分泌。因此，GSDMD孔通过静电过滤调节IL-1的释放，这表明除了大小外，电荷在通过这个大通道的货物运输中也是重要的。
As organelles of the innate immune system, Inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive lytic cell death through pyroptosis. Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. These structures reveal the different conformations of the two states, as well as extensive membrane-binding elements including a hydrophobic anchor and three positively charged patches. The GSDMD pore conduit is predominantly negatively charged. By contrast, IL-1 precursors possess an acidic domain that is proteolytically removed by caspase-1. When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged ones of similar sizes, and the pores favour the passage of IL-1β and IL-18 over that of their precursors. Consistent with these findings, living - but not pyroptotic - macrophages preferentially release mature IL-1β upon perforation by GSDMD. Mutation of the acidic residues of GSDMD compromises this preference, hindering intracellular retention of the precursor and secretion of the mature cytokine. Therefore, the GSDMD pore mediates IL-1 release by electrostatic filtering, which suggests the importance of charge in addition to size in the transport of cargoes across this large channel.
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影响因子：
48
作者：
Kucukelbir, Alp;Sigworth, Fred J.;Tagare, Hemant D.
通讯作者：
Tagare, Hemant D.
DOI：
10.1038/s41573-021-00154-z
发表时间：
2021-05
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Liu X;Xia S;Zhang Z;Wu H;Lieberman J
通讯作者：
Lieberman J
形成孔的蛋白质加油D可以调节白细胞介素-1的巨噬细胞分泌。
影响因子：
32.4
作者：
Evavold CL;Ruan J;Tan Y;Xia S;Wu H;Kagan JC
通讯作者：
Kagan JC
Gasdermin A3膜孔的冷冻EM结构。
影响因子：
64.8
作者：
Ruan J;Xia S;Liu X;Lieberman J;Wu H
通讯作者：
Wu H
DOI：
10.1073/pnas.1607769113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Aglietti, Robin A.;Estevez, Alberto;Dueber, Erin C.
通讯作者：
Dueber, Erin C.