xiap regulates cytosol-specific innate immunity to listeria infectionxiap调节cytosol-specific先天免疫李斯特菌感染.pdf

XIAP Regulates Cytosol-Specific Innate Immunity to Listeria Infection 1 2 1 Laura D. Bauler , Colin S. Duckett , Mary X. D. O’Riordan * 1 Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 2 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America Abstract 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-kB 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-kB–dependent signaling. Citation: Bauler LD, Duckett CS, O’Riordan MXD (2008) XIAP Regulates Cytosol-Specific Innate Immunity to Listeria Infection. PLoS Pathog 4(8): e1000142. doi:10.1371/journal.ppat.1000142 Editor: Pascale Co