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Cited by 236

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Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation

Open access
Van Opdenbosch, Nina, Gurung, Prajwal, Vande Walle, Lieselotte, Fossoul, Amelie, Kanneganti, Thirumala-Devi, Lamkanfi, Mohamed·2014·Nature Communications

Abstract

Despite its clinical importance in infection and autoimmunity, the activation mechanisms of the NLRP1b inflammasome remain enigmatic. Here we show that deletion of the inflammasome adaptor ASC in BALB/c mice and in C57BL/6 macrophages expressing a functional NLRP1b prevents anthrax lethal toxin (LeTx)-induced caspase-1 autoproteolysis and speck formation. However, ASC−/− macrophages undergo normal LeTx-induced pyroptosis and secrete significant amounts of interleukin (IL)-1β. In contrast, ASC is critical for caspase-1 autoproteolysis and IL-1β secretion by the NLRC4, NLRP3 and AIM2 inflammasomes. Notably, LeTx-induced inflammasome activation is associated with caspase-1 ubiquitination, which is unaffected in ASC-deficient cells. In vivo, ASC-deficient mice challenged with LeTx produce significant levels of IL-1β, IL-18 and HMGB1 in circulation, although caspase-1 autoproteolysis is abolished. As a result, ASC−/− mice are sensitive to rapid LeTx-induced lethality. Together, these results demonstrate that ASC-driven caspase-1 autoprocessing and speck formation are dispensable for the activation of caspase-1 and the NLRP1b inflammasome. The NLRP1b inflammasome activation may lead to pyroptosis and secretion of the inflammatory cytokines IL-1ß and IL-18 but the mechanisms behind these processes are not fully understood. Here, the authors show that they can occur independently of the inflammasome adaptor ASC and without caspase-1 autoprocessing.

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Metadata

Authors
Van Opdenbosch, N., Gurung, P., Vande Walle, L., Fossoul, A., Kanneganti, T.-D., & Lamkanfi, M.
Venue
Nature Communications
Published
2014-02-04
Volume
5
Issue
1
Pages
3209-3209
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2019407752
Cited by
236
References
6
FWCI
8.27
Type
journal article
Language
en
Open access
hybrid

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CoChat. (2026). Citation check: Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation. https://app.cochat.ai/papers/10.1038/ncomms4209
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Van Opdenbosch, N., Gurung, P., Vande Walle, L., Fossoul, A., Kanneganti, T.-D., & Lamkanfi, M. (2014). Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation. Nature Communications. https://doi.org/10.1038/ncomms4209

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