Structural insights into cytokine cleavage by inflammatory caspase-4

Pascal Devant, Ying Dong, Julian Mintseris, Weiyi Ma, Steven P. Gygi, Hao Wu () and Jonathan C. Kagan ()
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Pascal Devant: Boston Children’s Hospital and Harvard Medical School
Ying Dong: Harvard Medical School
Julian Mintseris: Harvard Medical School
Weiyi Ma: Boston Children’s Hospital and Harvard Medical School
Steven P. Gygi: Harvard Medical School
Hao Wu: Harvard Medical School
Jonathan C. Kagan: Boston Children’s Hospital and Harvard Medical School

Nature, 2023, vol. 624, issue 7991, 451-459

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06751-9

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