1. The tetrapeptide sequence of IL-18 and IL-1β regulates their recruitment and activation by inflammatory caspases
- Author
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Patrick M. Exconde, Claudia Hernandez-Chavez, Christopher M. Bourne, Rachel M. Richards, Mark B. Bray, Jan L. Lopez, Tamanna Srivastava, Marisa S. Egan, Jenna Zhang, William Yoo, Sunny Shin, Bohdana M. Discher, and Cornelius Y. Taabazuing
- Subjects
CP: Immunology ,Biology (General) ,QH301-705.5 - Abstract
Summary: Inflammasomes are multiprotein signaling complexes that activate the innate immune system. Canonical inflammasomes recruit and activate caspase-1, which then cleaves and activates IL-1β and IL-18, as well as gasdermin D (GSDMD) to induce pyroptosis. In contrast, non-canonical inflammasomes, caspases-4/-5 (CASP4/5) in humans and caspase-11 (CASP11) in mice, are known to cleave GSDMD, but their role in direct processing of other substrates besides GSDMD has remained unknown. Here, we show that CASP4/5 but not CASP11 can directly cleave and activate IL-18. However, CASP4/5/11 can all cleave IL-1β to generate a 27-kDa fragment that deactivates IL-1β signaling. Mechanistically, we demonstrate that the sequence identity of the tetrapeptide sequence adjacent to the caspase cleavage site regulates IL-18 and IL-1β recruitment and activation. Altogether, we have identified new substrates of the non-canonical inflammasomes and reveal key mechanistic details regulating inflammation that may aid in developing new therapeutics for immune-related disorders.
- Published
- 2023
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