美国波士顿儿童医院和哈佛医学院Jonathan C. Kagan和美国哈佛医学院Hao Wu共同合作，近期取得重要工作进展。他们开展了对炎性caspase-4剪切细胞因子的结构研究。相关研究成果2023年11月22日在线发表于《自然》杂志上。

据介绍，炎症半胱天冬酶（caspases）是哺乳动物先天免疫中的关键酶，控制白细胞介素-1（IL-1）家族细胞因子的处理和释放。尽管具有生物学重要性，但炎症caspases介导的细胞因子处理的结构基础仍不清楚。到目前为止，IL-1家族成员的催化裂解，包括pro-IL-1β和pro-IL-18，主要归因于典型炎症小体中的胱天蛋白酶-1（caspase-1）活性。

研究人员证明了来自人类和其他哺乳动物物种（啮齿类动物除外）的脂多糖受体胱天蛋白酶-4（caspase-4）能以类似于原型IL-1转化酶caspase-1切割pro-IL-1β和pro-IL-18的效率切割pro-IL-18。caspase-4切割pro-IL-18的这种能力，加上其先前定义的切割和激活裂解性成孔蛋白gasdermin D（GSDMD）的能力，使人类细胞能够绕过对典型炎症小体和caspase-1释放IL-18的需要。使用冷冻电镜确定的caspase-4–pro-IL-18复合物的结构显示，pro-lL-18通过两个不同的界面与caspase-4相互作用：蛋白酶外泌体和caspase酶活性位点的界面，该界面涉及pro-IL-1 8的前结构域中的残基，包括四肽caspase识别序列。所揭示的细胞因子底物捕获和切割的机制不同于对caspase底物GSDMD所观察到的机制。

总之，这些发现为讨论caspase在健康和疾病中的活性提供了一个结构框架。

附：英文原文

Title: Structural insights into cytokine cleavage by inflammatory caspase-4

Author: Devant, Pascal, Dong, Ying, Mintseris, Julian, Ma, Weiyi, Gygi, Steven P., Wu, Hao, Kagan, Jonathan C.

Issue&Volume: 2023-11-22

Abstract: Inflammatory caspases are key enzymes in mammalian innate immunity that control the processing and release of interleukin-1 (IL-1)-family cytokines1,2. Despite the biological importance, the structural basis for inflammatory caspase-mediated cytokine processing has remained unclear. To date, catalytic cleavage of IL-1-family members, including pro-IL-1β and pro-IL-18, has been attributed primarily to caspase-1 activities within canonical inflammasomes3. Here we demonstrate that the lipopolysaccharide receptor caspase-4 from humans and other mammalian species (except rodents) can cleave pro-IL-18 with an efficiency similar to pro-IL-1β and pro-IL-18 cleavage by the prototypical IL-1-converting enzyme caspase-1. This ability of caspase-4 to cleave pro-IL-18, combined with its previously defined ability to cleave and activate the lytic pore-forming protein gasdermin D (GSDMD)4,5, enables human cells to bypass the need for canonical inflammasomes and caspase-1 for IL-18 release. The structure of the caspase-4–pro-IL-18 complex determined using cryogenic electron microscopy reveals that pro-lL-18 interacts with caspase-4 through two distinct interfaces: a protease exosite and an interface at the caspase-4 active site involving residues in the pro-domain of pro-IL-18, including the tetrapeptide caspase-recognition sequence6. The mechanisms revealed for cytokine substrate capture and cleavage differ from those observed for the caspase substrate GSDMD7,8. These findings provide a structural framework for the discussion of caspase activities in health and disease. The human lipopolysaccharide receptor caspase-4 captures its cytokine substrate pro-IL-18 via a mechanism that is distinct from known caspase–substrate interactions, leading to inflammasome-independent IL-18 release from macrophages.

DOI: 10.1038/s41586-023-06751-9

Source: https://www.nature.com/articles/s41586-023-06751-9