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Nat Commun. 2014;5:3209. doi: 10.1038/ncomms4209.

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

Author information

1
1] Department of Medical Protein Research, VIB, Ghent B-9000, Belgium [2] Department of Biochemistry, Ghent University, Ghent B-9000, Belgium.
2
Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
3
1] Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA [2].
4
1] Department of Medical Protein Research, VIB, Ghent B-9000, Belgium [2] Department of Biochemistry, Ghent University, Ghent B-9000, Belgium [3].

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.

PMID:
24492532
PMCID:
PMC3926011
DOI:
10.1038/ncomms4209
[Indexed for MEDLINE]
Free PMC Article

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