Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation.
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.
1] Department of Medical Protein Research, VIB, Ghent B-9000, Belgium [2] Department of Biochemistry, Ghent University, Ghent B-9000, Belgium.
Nina
N
Van Opdenbosch
Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Prajwal
P
Gurung
1] Department of Medical Protein Research, VIB, Ghent B-9000, Belgium [2] Department of Biochemistry, Ghent University, Ghent B-9000, Belgium.
Lieselotte
L
Vande Walle
1] Department of Medical Protein Research, VIB, Ghent B-9000, Belgium [2] Department of Biochemistry, Ghent University, Ghent B-9000, Belgium.
Amelie
A
Fossoul
1] Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA [2].
Thirumala-Devi
TD
Kanneganti
1] Department of Medical Protein Research, VIB, Ghent B-9000, Belgium [2] Department of Biochemistry, Ghent University, Ghent B-9000, Belgium [3].
Mohamed
M
Lamkanfi
D000818:Animals; D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001427:Bacterial Toxins; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism*; D016923:Cell Death; D005260:Female; D024243:HMGB1 Protein / Q000097:blood; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D059748:Proteolysis; D013154:Spleen / Q000378:metabolism; D054875:Ubiquitination
D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; D053468:CARD Signaling Adaptor Proteins; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C509168:Nalp1b protein, mouse; C498534:Pycard protein, mouse; C030325:anthrax toxin; D020170:Caspase 1