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.
LeBlanc
Philippe M
PM
Department of Medicine, Division of Critical Care, and Centre for Study of Host Resistance, McGill University, Montreal H3A 1A1, Canada.
Yeretssian
Garabet
G
Rutherford
Nancy
N
Doiron
Karine
K
Nadiri
Amal
A
Zhu
Lei
L
Green
Douglas R
DR
Gruenheid
Samantha
S
Saleh
Maya
M
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis*; D053454:Caspase 12 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D044082:Citrobacter rodentium / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology; D005260:Female; D006801:Humans; D018928:Immunity, Mucosal / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology*; D011485:Protein Binding; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D053454:Caspase 12