title: Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome.
abstract: NLRP3 forms an inflammasome with its adaptor ASC, and its excessive activation can cause inflammatory diseases. However, little is known about the mechanisms that control assembly of the inflammasome complex. Here we show that microtubules mediated assembly of the NLRP3 inflammasome. Inducers of the NLRP3 inflammasome caused aberrant mitochondrial homeostasis to diminish the concentration of the coenzyme NAD(+), which in turn inactivated the NAD(+)-dependent α-tubulin deacetylase sirtuin 2; this resulted in the accumulation of acetylated α-tubulin. Acetylated α-tubulin mediated the dynein-dependent transport of mitochondria and subsequent apposition of ASC on mitochondria to NLRP3 on the endoplasmic reticulum. Therefore, in addition to direct activation of NLRP3, the creation of optimal sites for signal transduction by microtubules is required for activation of the entire NLRP3 inflammasome.
authors.affiliation: Laboratory of Host Defense, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Misawa
authors.forename: Michihiro
authors.initials: M
authors.lastname: Takahama
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kozaki
authors.forename: Hanna
authors.initials: H
authors.lastname: Lee
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D000107:Acetylation; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D003595:Cytoplasmic Streaming; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004398:Dyneins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D009243:NAD / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction; D056565:Sirtuin 2 / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D014404:Tubulin; D009243:NAD; D056565:Sirtuin 2; D004398:Dyneins