Multiple roles of CLAN (caspase-associated recruitment domain, leucine-rich repeat, and NAIP CIIA HET-E, and TP1-containing protein) in the mammalian innate immune response.
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.
Damiano
Jason S
JS
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Newman
Ruchi M
RM
Reed
John C
JC
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016923:Cell Death / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D007113:Immunity, Innate; D007375:Interleukin-1 / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D000070576:NLR Proteins; D009419:Nerve Tissue Proteins / Q000502:physiology*; D051616:Neuronal Apoptosis-Inhibitory Protein; D010457:Peptidoglycan / Q000494:pharmacology; D020449:Repetitive Sequences, Amino Acid; D012477:Salmonella enteritidis / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D012763:Shigella flexneri / Q000276:immunology; D013949:Thymus Extracts / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; C496800:NAIP protein, human; D000070576:NLR Proteins; C435692:NLRC4 protein, human; C427903:NLRP1 protein, human; D009419:Nerve Tissue Proteins; D051616:Neuronal Apoptosis-Inhibitory Protein; D010457:Peptidoglycan; D013949:Thymus Extracts; C031407:thymostimulin; D007930:Leucine