title: Apoptosis-associated speck-like protein containing a CARD forms specks but does not activate caspase-1 in the absence of NLRP3 during macrophage swelling.
abstract: Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is a key adaptor molecule required for the inflammatory processes. ASC acts by bridging NLRP proteins, such as NLRP3, with procaspase-1 within the inflammasome complex, which subsequently results in the activation of caspase-1 and the secretion of IL-1β and IL-18. In response to bacterial infection, ASC also forms specks by self-oligomerization to activate caspase-1 and induce pyroptosis. Hitherto, the role of these specks in NLRP3 inflammasome activation in response to danger signals, such as a hypotonic environment, largely has been unexplored. In this article, we report that, under hypotonic conditions and independently of NLRP3, ASC was able to form specks that did not activate caspase-1. These specks were not associated with pyroptosis and were controlled by transient receptor potential vanilloid 2 channel-mediated signaling. However, interaction with NLRP3 enhanced ASC speck formation, leading to fully functional inflammasomes and caspase-1 activation. This study reveals that the ASC speck can present different oligomerization assemblies and represents an essential step in the activation of functional NLRP3 inflammasomes.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
authors.forename: Vincent
authors.initials: V
authors.lastname: Compan
authors.affiliation: Unidad de Inflamación y Cirugía Experimental, Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria-Arrixaca, 30120 Murcia, Spain pablo.pelegrin@ffis.es fatima.martin@ffis.es.
authors.forename: Fátima
authors.initials: F
authors.lastname: Martín-Sánchez
authors.affiliation: Unidad de Inflamación y Cirugía Experimental, Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria-Arrixaca, 30120 Murcia, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Baroja-Mazo
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
authors.forename: Gloria
authors.initials: G
authors.lastname: López-Castejón
authors.affiliation: Unidad de Inflamación y Cirugía Experimental, Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria-Arrixaca, 30120 Murcia, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Gomez
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
authors.forename: Alexei
authors.initials: A
authors.lastname: Verkhratsky
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
authors.forename: David
authors.initials: D
authors.lastname: Brough
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and Unidad de Inflamación y Cirugía Experimental, Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria-Arrixaca, 30120 Murcia, Spain pablo.pelegrin@ffis.es fatima.martin@ffis.es.
authors.forename: Pablo
authors.identifier: http://orcid.org/0000-0002-9688-1804
authors.initials: P
authors.lastname: Pelegrín
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D015220:Calcium Channels / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D015220:Calcium Channels; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D050916:TRPV Cation Channels; C485717:Trpv2 protein, mouse; D020170:Caspase 1