Journal
JOURNAL OF IMMUNOLOGY
Volume 194, Issue 3, Pages 1261-1273Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1301676
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Funding
- Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica + Instituto Salud Carlos III-Fondo Europeo de Desarrollo Regional [EMER07/049, PI09/0120]
- Fundacion Seneca [11922/PI/09]
- European Research Council [ERC-2013-CoG 614578]
- Wellcome Trust
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Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is a key adaptor molecule required for the inflammatory processes. ASC acts by bridging NLRP proteins, such as NLRP3, with procaspase-1 within the inflammasome complex, which subsequently results in the activation of caspase-1 and the secretion of IL-1 beta and IL-18. In response to bacterial infection, ASC also forms specks by self-oligomerization to activate caspase-1 and induce pyroptosis. Hitherto, the role of these specks in NLRP3 inflammasome activation in response to danger signals, such as a hypotonic environment, largely has been unexplored. In this article, we report that, under hypotonic conditions and independently of NLRP3, ASC was able to form specks that did not activate caspase-1. These specks were not associated with pyroptosis and were controlled by transient receptor potential vanilloid 2 channel-mediated signaling. However, interaction with NLRP3 enhanced ASC speck formation, leading to fully functional inflammasomes and caspase-1 activation. This study reveals that the ASC speck can present different oligomerization assemblies and represents an essential step in the activation of functional NLRP3 inflammasomes.
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