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

Nina Van Opdenbosch; Prajwal Gurung; Lieselotte Vande Walle; Amelie Fossoul; Thirumala-Devi Kanneganti; Mohamed Lamkanfi

doi:10.1038/ncomms4209

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

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

Nina Van Opdenbosch, Prajwal Gurung, Lieselotte Vande Walle, Amelie Fossoul, Thirumala-Devi Kanneganti and Mohamed Lamkanfi

Nature communications, Vol.5(1), pp.3209-3209

02/04/2014

DOI: 10.1038/ncomms4209

PMCID: PMC3926011

PMID: 24492532

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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.

Details

Title: Subtitle: Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation
Creators: Nina Van Opdenbosch - , Ghent B-9000
Prajwal Gurung - , Memphis, Tennessee 38105-2794
Lieselotte Vande Walle - , Ghent B-9000
Amelie Fossoul - , Ghent B-9000
Thirumala-Devi Kanneganti - , Memphis, Tennessee 38105-2794
Mohamed Lamkanfi - , Ghent B-9000
Resource Type: Journal article
Publication Details: Nature communications, Vol.5(1), pp.3209-3209
DOI: 10.1038/ncomms4209
PMID: 24492532
PMCID: PMC3926011
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: Nature Pub. Group
Language: English
Date published: 02/04/2014
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984094398102771

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