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

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 repea...

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Published in:Science (American Association for the Advancement of Science) Vol. 369; no. 6510
Main Authors: Magupalli, Venkat Giri, Negro, Roberto, Tian, Yuzi, Hauenstein, Arthur V, Di Caprio, Giuseppe, Skillern, Wesley, Deng, Qiufang, Orning, Pontus, Alam, Hasan B, Maliga, Zoltan, Sharif, Humayun, Hu, Jun Jacob, Evavold, Charles L, Kagan, Jonathan C, Schmidt, Florian I, Fitzgerald, Katherine A, Kirchhausen, Tom, Li, Yongqing, Wu, Hao
Format: Journal Article
Language:English
Published: United States 18.09.2020
Subjects:
Animals
DNA-Binding Proteins - metabolism
HEK293 Cells
Histone Deacetylase 6 - genetics
Histone Deacetylase 6 - metabolism
Humans
Immunologic Surveillance
Inflammasomes - immunology
Inflammasomes - metabolism
Lipopolysaccharides - immunology
Macrophages - immunology
Macrophages - metabolism
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Microtubule-Organizing Center - metabolism
Microtubules - metabolism
NLR Family, Pyrin Domain-Containing 3 Protein - genetics
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
Protein Transport
Pyrin - metabolism
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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Summary: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.
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ISSN:1095-9203
1095-9203
DOI:10.1126/science.aas8995