Caspase-12 modulates NOD signaling and regulates antimicrobial peptide production and mucosal immunity.

Bacterial sensing by intracellular Nod proteins and other Nod-like receptors (NLRs) activates signaling pathways that mediate inflammation and pathogen clearance. Nod1 and Nod2 associate with the kinase Rip2 to stimulate NF-kappaB signaling. Other cytosolic NLRs assemble caspase-1-activating multiprotein complexes termed inflammasomes. Caspase-12 modulates the caspase-1 inflammasome, but unlike other NLRs, ...
Nod1 and Nod2 have not been linked to caspases, and mechanisms regulating the Nod-Rip2 complex are less clear. We report that caspase-12 dampens mucosal immunity to bacterial infection independent of its effects on caspase-1. Caspase-12 deficiency enhances production of antimicrobial peptides, cytokines, and chemokines to entric pathogens, an effect dependent on bacterial type III secretion and the Nod pathway. Mechanistically, caspase-12 binds to Rip2, displacing Traf6 from the signaling complex, inhibiting its ubiquitin ligase activity, and blunting NF-kappaB activation. Nod activation and resulting antimicrobial peptide production constitute an early innate defense mechanism, and caspase-12 inhibits this mucosal antimicrobial response.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Antimicrobial Cationic Peptides, Caspase 12, Citrobacter rodentium, Cytokines, Enterobacteriaceae Infections, Epithelial Cells, Female, Humans, Immunity, Mucosal, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Nod1 Signaling Adaptor Protein, Nod2 Signaling Adaptor Protein, Protein Binding, Receptor-Interacting Protein Serine-Threonine Kinases, TNF Receptor-Associated Factor 6
Cell Host Microbe
Date: Mar. 13, 2008
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