1. Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation.
- Author
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Lee BL, Stowe IB, Gupta A, Kornfeld OS, Roose-Girma M, Anderson K, Warming S, Zhang J, Lee WP, and Kayagaki N
- Subjects
- Animals, Apoptosis Regulatory Proteins genetics, Caspases genetics, Caspases, Initiator, Gene Knock-In Techniques, Gram-Negative Bacteria immunology, Gram-Negative Bacterial Infections genetics, Gram-Negative Bacterial Infections immunology, Gram-Negative Bacterial Infections pathology, Inflammasomes genetics, Intracellular Signaling Peptides and Proteins, Lipopolysaccharides immunology, Macrophages microbiology, Macrophages pathology, Mice, Mice, Knockout, Phosphate-Binding Proteins, Apoptosis Regulatory Proteins immunology, Caspases immunology, Inflammasomes immunology, Macrophages immunology, Proteolysis
- Abstract
Intracellular LPS sensing by caspase-4/5/11 triggers proteolytic activation of pore-forming gasdermin D (GSDMD), leading to pyroptotic cell death in Gram-negative bacteria-infected cells. Involvement of caspase-4/5/11 and GSDMD in inflammatory responses, such as lethal sepsis, makes them highly desirable drug targets. Using knock-in (KI) mouse strains, we herein provide genetic evidence to show that caspase-11 auto-cleavage at the inter-subunit linker is essential for optimal catalytic activity and subsequent proteolytic cleavage of GSDMD. Macrophages from caspase-11-processing dead KI mice ( Casp11
Prc D285A/D285A ) exhibit defective caspase-11 auto-processing and phenocopy Casp11-/- and caspase-11 enzymatically dead KI ( Casp11Enz C254A/C254A ) macrophages in attenuating responses to cytoplasmic LPS or Gram-negative bacteria infection. GsdmdD276A/D276A KI macrophages also fail to cleave GSDMD and are hypo-responsive to inflammasome stimuli, confirming that the GSDMD Asp276 residue is a nonredundant and indispensable site for proteolytic activation of GSDMD. Our data highlight the role of caspase-11 self-cleavage as a critical regulatory step for GSDMD processing and response against Gram-negative bacteria., (© 2018 Genentech.)- Published
- 2018
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