Abstract
Lysosome rupture triggers NLRP3 inflammasome activation in macrophages. However, the underlying mechanism is not fully understood. Here we showed that the TAK1-JNK pathway, a MAPK signaling pathway, is activated through lysosome rupture and that this activation is necessary for the complete activation of the NLRP3 inflammasome through the oligomerization of an adapter protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). We also revealed that the activation of the TAK1-JNK pathway is sustained through Ca(2+) ions and that calcium/calmodulin-dependent protein kinase type II functions upstream of the TAK1-JNK pathway and specifically regulates lysosome rupture-induced NLRP3 inflammasome activation. These data suggest a novel role for the TAK1-JNK pathway as a critical regulator of NLRP3 inflammasome activation.
Keywords:
Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII); Inflammasome; Innate Immunity; Lysosome Rupture; Mitogen-activated Protein Kinase (MAPK); NLRP3; Signal Transduction; TAK1; c-Jun N-terminal Kinase (JNK); siRNA Screen.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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CARD Signaling Adaptor Proteins
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Calcium / metabolism
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Tumor
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Cytoskeletal Proteins / chemistry
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Enzyme Activation
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HEK293 Cells
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Humans
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Immunoblotting
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Inflammasomes / metabolism*
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Lysosomes / metabolism*
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism*
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MAP Kinase Signaling System*
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Microscopy, Fluorescence
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NLR Family, Pyrin Domain-Containing 3 Protein
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Protein Multimerization
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RNA Interference
Substances
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AIM2 protein, human
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CARD Signaling Adaptor Proteins
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Carrier Proteins
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Inflammasomes
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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PYCARD protein, human
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Calcium