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.

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Figure 1: Inhibitors of tubulin polymerization specifically suppress activation of the NLRP3 inflammasome.
Figure 2: Microtubules mediate the approximation of ASC on mitochondria to NLRP3 on the endoplasmic reticulum in response to inducers of the NLRP3 inflammasome.
Figure 3: Dynein mediates the approximation of ASC on mitochondria to NLRP3 on the endoplasmic reticulum in response to inducers of the NLRP3 inflammasome.
Figure 4: Inducers of the NLRP3 inflammasome cause accumulation of acetylated α-tubulin in the perinuclear region.
Figure 5: Involvement of MEC-17 in activation of the NLRP3 inflammasome.
Figure 6: Acetylated α-tubulin and mitochondria accumulate in the perinuclear region after inactivation of SIRT2.
Figure 7: Loss of intracellular NAD+ promotes activation of the NLRP3 inflammasome.
Figure 8: Mitochondrial damage results in a lower abundance of intracellular NAD+.

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Acknowledgements

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.).

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T.M. did most of the experiments and analyzed the data; M.T., T.K., H.L. and J.Z. helped with the experiments; T.M. and T.S. designed most of the experiments and wrote the manuscript; and S.A. supervised the overall research project.

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Correspondence to Tatsuya Saitoh or Shizuo Akira.

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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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