@article{be0d2e4ff34842b29b41e4b1964b2ab7,
title = "HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation",
abstract = "Inflammasomes are supramolecular complexes that play key roles in immune surveillance. This is accomplished by the activation of inflammatory caspases, which leads to the proteolytic maturation of interleukin 1b (IL-1b) and pyroptosis. Here, we show that nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3)- and pyrin-mediated inflammasome assembly, caspase activation, and IL-1b conversion occur at the microtubule-organizing center (MTOC). Furthermore, the dynein adapter histone deacetylase 6 (HDAC6) is indispensable for the microtubule transport and assembly of these inflammasomes both in vitro and in mice. Because HDAC6 can transport ubiquitinated pathological aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for the down-regulation of these inflammasomes by autophagy. This work suggests an unexpected parallel between the formation of physiological and pathological aggregates.",
keywords = "pyrin inflammasome activation, supramolecular complexes, immune surveillance, NLRP3, autophagy",
author = "Magupalli, {Venkat Giri} and Roberto Negro and Yuzi Tian and Hauenstein, {Arthur V.} and Caprio, {Giuseppe Di} and Wesley Skillern and Qiufang Deng and Pontus Orning and Alam, {Hasan B.} and Zoltan Maliga and Humayun Sharif and Hu, {Jun Jacob} and Evavold, {Charles L.} and Kagan, {Jonathan C.} and Schmidt, {Florian I.} and Fitzgerald, {Katherine A.} and Tom Kirchhausen and Yongqing Li and Hao Wu",
note = "Funding Information: We thank J. Shah (Harvard Medical School), T. Mitchison (Harvard Medical School), and R. Vale (UCSF) for discussions; R. Mazitschek (Harvard Medical School) for discussions on HDAC inhibitors; G. Nu{\~n}ez (University of Michigan) for Nek7−/− iBMDMs and for cDNA encoding human caspase-1; J. Yuan (Harvard Medical School) for cDNA encoding human IL-1b; M. Dong (Boston Children's Hospital) for recombinant full-length TcdB toxin; P. Matthias (Friedrich Miescher Institute for Biomedical Research) for human HDAC6 and mouse Hdac6 plasmids; Y. Zhang and J. Lieberman (Boston Children's Hospital) for anesthetizing and dissecting out the bones from mice; K. Rhee (Seoul National University) for NEK7 antibody; HCIA/HHMI summer institute, Woods Hole, and H. Leung (Optical Microscopy Core Facility of Program in Cellular and Molecular Medicine, Boston Children's Hospital) for help with laser scanning confocal microscopy; J. Waters and T. Lambert (Nikon Imaging Center, Harvard Medical School) for help with live-cell microscopy; R. Mathieu (Flow Cytometry Research Facility, Boston Children's Hospital) for help with cell sorting and cell analysis; and M. Ericsson (Electron Microscopy Core Facility, Harvard Medical School) for help with transmission electron microscopy. Funding: This work was supported by the National Institutes of Health (grant nos. HD087988 and AI124491 to H.W., MIRA award no. GM130386 to T.K., and a T32 training fellowship to A.V.H.), Biogen (SRA to T.K.), and the Joint Institute of University of Michigan and Peking University Health Science Center (grant no. U068874 to Y.L.). T.K. acknowledges support from the Janelia Visitor Program and E. Betzig, E. Marino, T. Liu, G. Upadhyayula, and W. Legant for help and advice in constructing and installing the LLSM. Construction of the LLSM was supported by grants from Biogen and Ionis Pharmaceuticals to T.K. Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",
year = "2020",
month = sep,
day = "18",
doi = "10.1126/SCIENCE.AAS8995",
language = "English",
volume = "369",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6509",
}