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

Philippe M LeBlanc; Garabet Yeretssian; Nancy Rutherford; Karine Doiron; Amal Nadiri; Lei Zhu; Douglas R Green; Samantha Gruenheid; Maya Saleh

doi:10.1016/j.chom.2008.02.004

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

Cell Host Microbe. 2008 Mar 13;3(3):146-57. doi: 10.1016/j.chom.2008.02.004.

Authors

Philippe M LeBlanc¹, Garabet Yeretssian, Nancy Rutherford, Karine Doiron, Amal Nadiri, Lei Zhu, Douglas R Green, Samantha Gruenheid, Maya Saleh

Affiliation

¹ Department of Medicine, Division of Critical Care, and Centre for Study of Host Resistance, McGill University, Montreal H3A 1A1, Canada.

PMID: 18329614
DOI: 10.1016/j.chom.2008.02.004

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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 Kinase 2
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
TNF Receptor-Associated Factor 6 / metabolism

Substances

Adaptor Proteins, Signal Transducing
Antimicrobial Cationic Peptides
Cytokines
NF-kappa B
Nod1 Signaling Adaptor Protein
Nod1 protein, mouse
Nod2 Signaling Adaptor Protein
Nod2 protein, mouse
TNF Receptor-Associated Factor 6
Receptor-Interacting Protein Serine-Threonine Kinase 2
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk2 protein, mouse
Caspase 12