Abstract
NAIP CIIA HET-E and TP1 (NACHT) family proteins are involved in sensing intracellular pathogens or pathogen-derived molecules, triggering host defense responses resulting in caspase-mediated processing of proinflammatory cytokines and NF-kappaB activation. Caspase-associated recruitment domain, leucine-rich repeat, and NACHT-containing protein (CLAN), also known as ICE protease-activating factor, belongs to a branch of the NACHT family that contains proteins carrying caspase-associated recruitment domains (CARDs) and leucine-rich repeats (LRRs). By using gene transfer and RNA-interference approaches, we demonstrate in this study that CLAN modulates endogenous caspase-1 activation and subsequent IL-1beta secretion from human macrophages after exposure to LPS, peptidoglycan, and pathogenic bacteria. CLAN was also found to mediate a direct antibacterial effect within macrophages after Salmonella infection and to sensitize host cells to Salmonella-induced cell death through a caspase-1-independent mechanism. These results indicate that CLAN contributes to several biological processes central to host defense, suggesting a prominent role for this NACHT family member in innate immunity.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / physiology*
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Adjuvants, Immunologic / biosynthesis
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Adjuvants, Immunologic / deficiency
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / physiology
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Calcium-Binding Proteins / biosynthesis
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Calcium-Binding Proteins / deficiency
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / physiology*
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Cell Death / immunology
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Cell Line, Tumor
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Humans
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Immunity, Innate
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Interleukin-1 / metabolism
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Leucine / metabolism
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Lipopolysaccharides / pharmacology
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / microbiology
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NLR Proteins
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Nerve Tissue Proteins / physiology*
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Neuronal Apoptosis-Inhibitory Protein
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Peptidoglycan / pharmacology
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Repetitive Sequences, Amino Acid
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Salmonella enteritidis / immunology
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Salmonella typhimurium / immunology
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Shigella flexneri / immunology
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Thymus Extracts / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Adjuvants, Immunologic
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Calcium-Binding Proteins
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Interleukin-1
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Lipopolysaccharides
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NAIP protein, human
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NLR Proteins
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NLRC4 protein, human
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NLRP1 protein, human
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Nerve Tissue Proteins
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Neuronal Apoptosis-Inhibitory Protein
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Peptidoglycan
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Thymus Extracts
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thymostimulin
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Leucine