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.
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We thank T. Kitamura (Tokyo University) for Plat-E packaging cells; H. Osada and T. Saito (RIKEN Natural Products Depository) for the authentic chemical compound library of the RIKEN Natural Products Depository; T. Yoshimori and K. Ikegami for critical reading of the manuscript; and members of the Laboratory of Host Defense for assistance. Supported by Japan Society for the Promotion of Science Grant-in-Aid for Specially Promoted Research (S.A.), Japan Society for the Promotion of Science Funding Program for World-Leading Innovative R&D on Science and Technology 'FIRST Program' (S.A.) and Japan Science and Technology Agency Core Research for Evolutional Science and Technology (T.S.).
The authors declare no competing financial interests.
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Misawa, T., Takahama, M., Kozaki, T. et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol 14, 454–460 (2013). https://doi.org/10.1038/ni.2550
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