XIAP regulates cytosol-specific innate immunity to Listeria infection

• Published in: PLoS pathogens 2008-08, Vol.4 (8), p.e1000142-e1000142
• Main Authors: Bauler, Laura D, Duckett, Colin S, O'Riordan, Mary X D
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Bacterial infections; Cell receptors; Cells, Cultured; Cellular signal transduction; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Cytosol - immunology; Cytosol - metabolism; Development and progression; Immune system; Immunity, Innate - genetics; Immunology/Immunity to Infections; Immunology/Innate Immunity; Infectious Diseases/Bacterial Infections; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - immunology; JNK Mitogen-Activated Protein Kinases - metabolism; Listeria monocytogenes - immunology; Listeria monocytogenes - metabolism; Listeriosis; Listeriosis - genetics; Listeriosis - immunology; Listeriosis - metabolism; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Mice; Mice, Knockout; Microbiology; Microbiology/Immunity to Infections; Microbiology/Innate Immunity; NF-kappa B - genetics; NF-kappa B - immunology; Nod2 Signaling Adaptor Protein - agonists; Nod2 Signaling Adaptor Protein - genetics; Nod2 Signaling Adaptor Protein - immunology; Nod2 Signaling Adaptor Protein - metabolism; Physiological aspects; Proteins; Risk factors; Signal Transduction - genetics; Signal Transduction - immunology; Toll-Like Receptor 2 - agonists; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 2 - metabolism; X-Linked Inhibitor of Apoptosis Protein - genetics; X-Linked Inhibitor of Apoptosis Protein - immunology; X-Linked Inhibitor of Apoptosis Protein - metabolism
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000142

The inhibitor of apoptosis protein (IAP) family has been implicated in immune regulation, but the mechanisms by which IAP proteins contribute to immunity are incompletely understood. We show here that X-linked IAP (XIAP) is required for innate immune control of Listeria monocytogenes infection. Mice deficient in XIAP had a higher bacterial burden 48 h after infection than wild-type littermates, and exhibited substantially decreased survival. XIAP enhanced NF-kappaB activation upon L. monocytogenes infection of activated macrophages, and prolonged phosphorylation of Jun N-terminal kinase (JNK) specifically in response to cytosolic bacteria. Additionally, XIAP promoted maximal production of pro-inflammatory cytokines upon bacterial infection in vitro or in vivo, or in response to combined treatment with NOD2 and TLR2 ligands. Together, our data suggest that XIAP regulates innate immune responses to L. monocytogenes infection by potentiating synergy between Toll-like receptors (TLRs) and Nod-like receptors (NLRs) through activation of JNK- and NF-kappaB-dependent signaling.