小柯机器人

美国哈佛医学院Hao Wu、Jianbin Ruan等研究人员合作解析Gasdermin D孔结构。该研究于2021年4月21日在线发表于国际一流学术期刊《自然》。

研究人员表示，作为先天免疫系统的细胞器，炎症小体激活caspase-1和其他炎症性caspase从而切割gasdermin D（GSDMD）。caspase-1还切割白介素（IL）-1家族的无活性前体来产生成熟的细胞因子，例如IL-1β和IL-18。切开的GSDMD形成跨膜孔，使IL-1释放并通过焦亡驱动细胞裂解。

研究人员报道了GSDMD孔和前孔的冷冻电镜结构。这些结构揭示了两种状态的不同构象，以及广泛的膜结合元件，包括疏水性锚和三个带正电荷的膜片。 GSDMD孔导管主要带负电。相反，IL-1前体具有被caspase-1蛋白水解去除的酸性结构域。当通过GSDMD孔渗透时，未溶解的脂质体释放带正电荷和中性货物的速度要快于具有类似大小的带负电荷的货物，并且与它们的前体相比，孔更有利于IL-1β和IL-18的通过。

与这些发现一致的是，存活而非焦亡的的巨噬细胞在被GSDMD穿孔后会优先释放成熟的IL-1β。GSDMD酸性残基的突变损害了这种偏好，从而阻碍了前体的细胞内滞留和成熟细胞因子的分泌。因此，GSDMD孔通过静电过滤介导IL-1的释放，这表明该通道的货物运输中电荷的重要性。

附：英文原文

Title: Gasdermin D pore structure reveals preferential release of mature interleukin-1

Author: Shiyu Xia, Zhibin Zhang, Venkat Giri Magupalli, Juan Lorenzo Pablo, Ying Dong, Setu M. Vora, Longfei Wang, Tian-Min Fu, Matthew P. Jacobson, Anna Greka, Judy Lieberman, Jianbin Ruan, Hao Wu

Issue&Volume: 2021-04-21

Abstract: 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 cell lysis through pyroptosis1,2,3,4,5,6,7,8,9. 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 have an acidic domain that is proteolytically removed by caspase-110. When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes 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. The GSDMD pore therefore 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.

DOI: 10.1038/s41586-021-03478-3

Source: https://www.nature.com/articles/s41586-021-03478-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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