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HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation.

Science (New York, N.Y.)

Authors: Venkat Giri Magupalli, Roberto Negro, Yuzi Tian, Arthur V Hauenstein, Giuseppe Di Caprio, Wesley Skillern, Qiufang Deng, Pontus Orning, Hasan B Alam, Zoltan Maliga, Humayun Sharif, Jun Jacob Hu, Charles L Evavold, Jonathan C Kagan, Florian I Schmidt, Katherine A Fitzgerald, Tom Kirchhausen, Yongqing Li, Hao Wu

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 1β (IL-1β) 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-1β 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.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PMID: 32943500

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