北京生命科学研究所Feng Shao等近期取得重要工作进展。他们研究提出了Caspase-4 非典型炎症小体对IL-18的识别和成熟机制。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，经典的（caspase-1）和非经典的（包括caspase 4、5和11；以下称为caspase 4/5/11）炎症小体都切割gasdermin D（GSDMD）以诱导细胞焦亡。虽然caspase-1处理IL-1β和IL-18以实现成熟，但脂多糖激活的caspase-4/5/11尚未确定细胞因子靶标。

研究人员发现激活的人caspase-4，而不是小鼠caspase-11，在体外和细菌感染期间直接有效地处理IL-18。caspase-4-pro-IL-18配合物的晶体结构揭示了一个二元底物识别机制;催化袋与四肽结合，并且一种独特的外源位点可以对GSDMD进行批判性识别，类似地与pro-IL-18中由前肽和后切割位点序列共同形成的特定结构结合。这种二元识别也被caspase-5和caspase-1用于处理pro-IL-18。在caspase-11中，外泌体周围的结构偏差是其无法靶向pro-IL-18的原因，而pro-IL-1是通过合理设计的突变恢复的。pro-IL-18的结构具有前肽和切割后位点区域之间的自身抑制性相互作用，阻止IL-18Rα受体的识别。caspase-1、-4或-5的切割会导致IL-18的构象发生实质性变化，从而产生两个关键的受体结合位点。

总之，这一研究确定IL-18是脂多糖激活的caspase-4/5的靶标。这一发现改变了对非经典炎症小体介导的防御以及IL-18在免疫和疾病中的功能理解。

附：英文原文

Title: Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome

Author: Shi, Xuyan, Sun, Qichao, Hou, Yanjie, Zeng, Huan, Cao, Yong, Dong, Mengqiu, Ding, Jingjin, Shao, Feng

Issue&Volume: 2023-11-22

Abstract: The canonical (caspase-1) and noncanonical (comprising caspases 4, 5 and 11; hereafter, caspase-4/5/11) inflammasomes both cleave gasdermin D (GSDMD) to induce pyroptosis1,2. Whereas caspase-1 processes IL-1β and IL-18 for maturation3–6, no cytokine target has been firmly established for lipopolysaccharide-activated caspase-4/5/117–9. Here we show that activated human caspase-4, but not mouse caspase-11, directly and efficiently processes IL-18 in vitro and during bacterial infections. Caspase-4 cleaves the same tetrapeptide site in pro-IL-18 as caspase-1. The crystal structure of the caspase-4–pro-IL-18 complex reveals a two-site (binary) substrate-recognition mechanism; the catalytic pocket engages the tetrapeptide, and a unique exosite that critically recognizes GSDMD10 similarly binds to a specific structure formed jointly by the propeptide and post-cleavage-site sequences in pro-IL-18. This binary recognition is also used by caspase-5 as well as caspase-1 to process pro-IL-18. In caspase-11, a structural deviation around the exosite underlies its inability to target pro-IL-18, which is restored by rationally designed mutations. The structure of pro-IL-18 features autoinhibitory interactions between the propeptide and the post-cleavage-site region, preventing recognition by the IL-18Rα receptor. Cleavage by caspase-1, -4 or -5 induces substantial conformational changes of IL-18 to generate two critical receptor-binding sites. Our study establishes IL-18 as a target of lipopolysaccharide-activated caspase-4/5. The finding is paradigm shifting in the understanding of noncanonical-inflammasome-mediated defences and also the function of IL-18 in immunity and disease. Activated human caspase-4 directly and efficiently processes IL-18 in vitro and during bacterial infections, cleaving the same tetrapeptide site in pro-IL-18 as caspase-1.

DOI: 10.1038/s41586-023-06742-w

Source: https://www.nature.com/articles/s41586-023-06742-w