The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation.

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.

• Authors: Masahiro Okada, Atsushi Matsuzawa, Akihiko Yoshimura, Hidenori Ichijo
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 47 Pg. 32926-36 (Nov 21 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25288801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• AIM2 protein, human
• CARD Signaling Adaptor Proteins
• Carrier Proteins
• Cytoskeletal Proteins
• DNA-Binding Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• PYCARD protein, human
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• Calcium

Topics

• CARD Signaling Adaptor Proteins
• Calcium (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cytoskeletal Proteins (chemistry, genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Enzyme Activation
• HEK293 Cells
• Humans
• Immunoblotting
• Inflammasomes (metabolism)
• JNK Mitogen-Activated Protein Kinases (genetics, metabolism)
• Lysosomes (metabolism)
• MAP Kinase Kinase Kinases (genetics, metabolism)
• MAP Kinase Signaling System
• Microscopy, Fluorescence
• NLR Family, Pyrin Domain-Containing 3 Protein
• Protein Multimerization
• RNA Interference