8J6K

Crystal structure of pro-interleukin-18 and caspase-4 complex

This is a non-PDB format compatible entry.

Summary for 8J6K

• Entry DOI: 10.2210/pdb8j6k/pdb
• Descriptor: Caspase-4 subunit p20, Caspase-4 subunit p10, Interleukin-18, ... (4 entities in total)
• Functional Keywords: inflammatory cytokine, enzyme, immune system, hydrolase-immune system complex, hydrolase/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 70557.54

Authors

Sun, Q.,Hou, Y.J.,Ding, J. (deposition date: 2023-04-26, release date: 2023-11-29, Last modification date: 2023-12-27)

Primary citation

Shi, X.,Sun, Q.,Hou, Y.,Zeng, H.,Cao, Y.,Dong, M.,Ding, J.,Shao, F.
Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome.
Nature, 624:442-450, 2023

PubMed 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 pyroptosis. Whereas caspase-1 processes IL-1β and IL-18 for maturation, no cytokine target has been firmly established for lipopolysaccharide-activated caspase-4/5/11. 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 GSDMD 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.

PubMed: 37993714
DOI: 10.1038/s41586-023-06742-w

Experimental method

X-RAY DIFFRACTION (3.12 Å)