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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Article numberaas8995
JournalScience
Volume369
Issue number6509
DOIs
StatePublished - Sep 2020
Externally publishedYes

ASJC Scopus subject areas

  • General

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