8SPB

Caspase-4/Pro-IL-18 complex

Summary for 8SPB

• Entry DOI: 10.2210/pdb8spb/pdb
• EMDB information: 40678
• Descriptor: Caspase-4 subunit p20, Caspase-4 subunit p10, Interleukin-18 (3 entities in total)
• Functional Keywords: innate immune, complex, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 111948.78

Authors

Pascal, D.,Dong, Y.,Wu, H.,Jon, K. (deposition date: 2023-05-02, release date: 2023-11-22, Last modification date: 2025-05-21)

Primary citation

Devant, P.,Dong, Y.,Mintseris, J.,Ma, W.,Gygi, S.P.,Wu, H.,Kagan, J.C.
Structural insights into cytokine cleavage by inflammatory caspase-4.
Nature, 624:451-459, 2023

PubMed Abstract: Inflammatory caspases are key enzymes in mammalian innate immunity that control the processing and release of interleukin-1 (IL-1)-family cytokines. 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 inflammasomes. 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), 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 sequence. The mechanisms revealed for cytokine substrate capture and cleavage differ from those observed for the caspase substrate GSDMD. These findings provide a structural framework for the discussion of caspase activities in health and disease.

PubMed: 37993712
DOI: 10.1038/s41586-023-06751-9

Experimental method

ELECTRON MICROSCOPY (3.2 Å)