The tetrapeptide sequence of IL-18 and IL-1β regulates their recruitment and activation by inflammatory caspases

  • Cell Rep. 2023 Dec 15;42(12):113581. doi: 10.1016/j.celrep.2023.113581.
Patrick M Exconde  1 ,  Claudia Hernandez-Chavez  1 ,  Christopher M Bourne  1 ,  Rachel M Richards  2 ,  Mark B Bray  1 ,  Jan L Lopez  3 ,  Tamanna Srivastava  1 ,  Marisa S Egan  2 ,  Jenna Zhang  2 ,  William Yoo  1 ,  Sunny Shin  2 ,  Bohdana M Discher  1 ,  Cornelius Y Taabazuing  4
Affiliations
  • 1. Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 2. Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 3. Department of Biology, Boston University, Boston, MA, USA.
  • 4. Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: [email protected].
PMID: 38103201 DOI: 10.1016/j.celrep.2023.113581
Abstract

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.

Keywords
CP: Immunology; IL-18; IL-1β; caspase-1; caspase-11; caspase-4; caspase-5; cytokines; inflammasomes; pyroptosis.
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