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 ()
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Nina Van Opdenbosch: VIB
Prajwal Gurung: St Jude Children's Research Hospital
Lieselotte Vande Walle: VIB
Amelie Fossoul: VIB
Thirumala-Devi Kanneganti: St Jude Children's Research Hospital
Mohamed Lamkanfi: VIB

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4209

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