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

Xuyan Shi, Qichao Sun, Yanjie Hou, Huan Zeng, Yong Cao, Mengqiu Dong, Jingjin Ding () and Feng Shao ()
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Xuyan Shi: National Institute of Biological Sciences, Beijing
Qichao Sun: Chinese Academy of Sciences
Yanjie Hou: Chinese Academy of Sciences
Huan Zeng: National Institute of Biological Sciences, Beijing
Yong Cao: National Institute of Biological Sciences, Beijing
Mengqiu Dong: National Institute of Biological Sciences, Beijing
Jingjin Ding: National Institute of Biological Sciences, Beijing
Feng Shao: National Institute of Biological Sciences, Beijing

Nature, 2023, vol. 624, issue 7991, 442-450

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06742-w

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