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

• Published in: Cell host & microbe 2008-03, Vol.3 (3), p.146-157
• Main Authors: LeBlanc, Philippe M, Yeretssian, Garabet, Rutherford, Nancy, Doiron, Karine, Nadiri, Amal, Zhu, Lei, Green, Douglas R, Gruenheid, Samantha, Saleh, Maya
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - immunology; Animals; Antimicrobial Cationic Peptides - biosynthesis; Caspase 12 - deficiency; Caspase 12 - immunology; Caspase 12 - metabolism; Citrobacter rodentium - immunology; Cytokines - biosynthesis; Enterobacteriaceae Infections - immunology; Enterobacteriaceae Infections - microbiology; Enterobacteriaceae Infections - pathology; Epithelial Cells - immunology; Epithelial Cells - microbiology; Female; Humans; Immunity, Mucosal - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; Nod1 Signaling Adaptor Protein - immunology; Nod2 Signaling Adaptor Protein - immunology; Protein Binding; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; TNF Receptor-Associated Factor 6 - metabolism
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2008.02.004

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.