Titre
Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner.
Type
article
Institution
Externe
Auteur(s)
Conos, S.A.
Auteure/Auteur
Chen, K.W.
Auteure/Auteur
De Nardo, D.
Auteure/Auteur
Hara, H.
Auteure/Auteur
Whitehead, L.
Auteure/Auteur
Núñez, G.
Auteure/Auteur
Masters, S.L.
Auteure/Auteur
Murphy, J.M.
Auteure/Auteur
Schroder, K.
Auteure/Auteur
Vaux, D.L.
Auteure/Auteur
Lawlor, K.E.
Auteure/Auteur
Lindqvist, L.M.
Auteure/Auteur
Vince, J.E.
Auteure/Auteur
Liens vers les personnes
ISSN
1091-6490
Statut éditorial
Publié
Date de publication
2017-02-07
Volume
114
Numéro
6
Première page
E961
Dernière page/numéro d’article
E969
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase-1 prevented MLKL-induced IL-1β secretion, they did not prevent necroptotic cell death. Gasdermin D (GSDMD), the pore-forming caspase-1 substrate required for efficient NLRP3-triggered pyroptosis and IL-1β release, was not essential for MLKL-dependent death or IL-1β secretion. Imaging of MLKL-dependent ASC speck formation demonstrated that necroptotic stimuli activate NLRP3 cell-intrinsically, indicating that MLKL-induced NLRP3 inflammasome formation and IL-1β cleavage occur before cell lysis. Furthermore, we show that necroptotic activation of NLRP3, but not necroptotic cell death alone, is necessary for the activation of NF-κB in healthy bystander cells. Collectively, these results demonstrate the potential importance of NLRP3 inflammasome activity as a driving force for inflammation in MLKL-dependent diseases.
Sujets
PID Serval
serval:BIB_A49053FFE627
PMID
Open Access
Oui
Date de création
2018-09-22T19:03:03.058Z
Date de création dans IRIS
2025-05-21T03:49:18Z