Abstract
Inflammasomes regulate innate immune responses by facilitating maturation of inflammatory cytokines, interleukin (IL)-1β and IL-18. NACHT, LRR and PYD domains-containing protein 7 (NALP7) is one inflammasome constituent, but little is known about its cellular handling. Here we show a mechanism for NALP7 protein stabilization and activation of the inflammasome by Toll-like receptor (TLR) agonism with bacterial lipopolysaccharide (LPS) and the synthetic acylated lipopeptide Pam3CSK4. NALP7 is constitutively ubiquitinated and recruited to the endolysosome for degradation. With TLR ligation, the deubiquitinase enzyme, STAM-binding protein (STAMBP) impedes NALP7 trafficking to lysosomes to increase NALP7 abundance. STAMBP deubiquitinates NALP7 and STAMBP knockdown abrogates LPS or Pam3CSK4-induced increases in NALP7 protein. A small-molecule inhibitor of STAMBP deubiquitinase activity, BC-1471, decreases NALP7 protein levels and suppresses IL-1β release after TLR agonism. These findings describe a unique pathway of inflammasome regulation with the identification of STAMBP as a potential therapeutic target to reduce pro-inflammatory stress.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / immunology
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Cell Line
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Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors
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Endosomal Sorting Complexes Required for Transport / genetics*
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Endosomal Sorting Complexes Required for Transport / immunology
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Enzyme Inhibitors / pharmacology*
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / immunology
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Gene Expression Regulation
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HeLa Cells
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Humans
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Immunity, Innate
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Inflammasomes / antagonists & inhibitors
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Inflammasomes / genetics*
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Inflammasomes / immunology
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Interleukin-18 / genetics
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Interleukin-18 / immunology
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects*
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Leukocytes, Mononuclear / immunology
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Lipopeptides / antagonists & inhibitors
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Lipopeptides / pharmacology
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Lysosomes / drug effects
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Lysosomes / metabolism
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Molecular Docking Simulation
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Primary Cell Culture
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Signal Transduction
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THP-1 Cells
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Ubiquitin Thiolesterase / antagonists & inhibitors
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Ubiquitin Thiolesterase / genetics*
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Ubiquitin Thiolesterase / immunology
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Ubiquitination / drug effects
Substances
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Adaptor Proteins, Signal Transducing
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Endosomal Sorting Complexes Required for Transport
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Enzyme Inhibitors
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IL18 protein, human
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IL1B protein, human
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Inflammasomes
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Interleukin-18
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Interleukin-1beta
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Lipopeptides
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Lipopolysaccharides
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NLRP7 protein, human
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Pam(3)CSK(4) peptide
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STAMBP protein, human
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TLR4 protein, human
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Toll-Like Receptor 4
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Ubiquitin Thiolesterase