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Updated: Jun 26, 2025

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
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Structural transitions enable interleukin-18 maturation and signaling

Ying Dong1, Jeffrey P Bonin2, Pascal Devant3

  • 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.

Immunity
|May 11, 2024
PubMed

Several interleukin-1 (IL-1) family members, including IL-1β and IL-18, require processing by inflammasome-associated caspases to unleash their activities. Here, we unveil, by cryoelectron microscopy (cryo-EM), two major conformations of the complex between caspase-1 and pro-IL-18. One conformation is similar to the complex of caspase-4 and pro-IL-18, with interactions at both the active site and an exosite (closed conformation), and the other only contains interactions at the active site (open conformation). Thus, pro-IL-18 recruitment and processing by caspase-1 is less dependent on the exosite than the active site, unlike caspase-4. Structure determination by nuclear magnetic resonance uncovers a compact fold of apo pro-IL-18, which is similar to caspase-1-bound pro-IL-18 but distinct from cleaved IL-18. Binding sites for IL-18 receptor and IL-18 binding protein are only formed upon conformational changes after pro-IL-18 cleavage. These studies show how pro-IL-18 is selected as a caspase-1 substrate, and why cleavage is necessary for its inflammatory activity.

Keywords:
IL-18NMRcaspase-1conformational changecryo-EMcytokine cleavageinflammatory activitypro-IL-18

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