title: Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux.
abstract: Recognition of microbe-associated molecular patterns or endogenous danger signals by a subset of cytosolic PRRs results in the assembly of multiprotein signaling complexes, the so-called inflammasomes. Canonical inflammasomes are assembled by NOD-like receptor (NLR) or PYHIN family members and activate caspase-1, which promotes the induction of pyroptosis and the release of mature interleukin-1β/-18. Recently, a noncanonical inflammasome pathway was discovered that results in caspase-11 activation in response to bacterial lipopolysaccharide (LPS) in the cytosol. Interestingly, caspase-11 induces pyroptosis by itself, but requires NLRP3, the inflammasome adapter ASC, and caspase-1 to promote cytokine secretion. Here, we have studied the mechanism by which caspase-11 controls IL-1β secretion. Investigating NLRP3/ASC complex formation, we find that caspase-11 functions upstream of a canonical NLRP3 inflammasome. The activation of NLRP3 by caspase-11 during LPS transfection is a cell-intrinsic process and is independent of the release of danger signals. Furthermore, we show that active caspase-11 leads to a drop of intracellular potassium levels, which is necessary to activate NLRP3. Our study, therefore, sheds new light on the mechanism of noncanonical inflammasome signaling.
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rühl
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Petr
authors.initials: P
authors.lastname: Broz
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D053471:Caspases, Initiator; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D011188:Potassium
keywords: Caspase-11; Inflammasome; Interleukin-1 beta (IL-1β); Lipopolysaccharide; NLRP3; Potassium efflux; Pyroptosis