title: 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.affiliation: From the Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, the Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, and.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okada
authors.affiliation: From the Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, the Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan matsushi@m.tohoku.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
authors.affiliation: the Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, and.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: From the Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
mesh_terms: D053468:CARD Signaling Adaptor Proteins; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D058847:Inflammasomes / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008856:Microscopy, Fluorescence; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D055503:Protein Multimerization; D034622:RNA Interference; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000099151:MAP Kinase Kinase Kinase 7; C410167:AIM2 protein, human; C453881:NLRP3 protein, human; C402202:PYCARD protein, human
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