title: Inflammasome-dependent IL-1β release depends upon membrane permeabilisation.
abstract: Interleukin-1β (IL-1β) is a critical regulator of the inflammatory response. IL-1β is not secreted through the conventional ER-Golgi route of protein secretion, and to date its mechanism of release has been unknown. Crucially, its secretion depends upon the processing of a precursor form following the activation of the multimolecular inflammasome complex. Using a novel and reversible pharmacological inhibitor of the IL-1β release process, in combination with biochemical, biophysical, and real-time single-cell confocal microscopy with macrophage cells expressing Venus-labelled IL-1β, we have discovered that the secretion of IL-1β after inflammasome activation requires membrane permeabilisation, and occurs in parallel with the death of the secreting cell. Thus, in macrophages the release of IL-1β in response to inflammasome activation appears to be a secretory process independent of nonspecific leakage of proteins during cell death. The mechanism of membrane permeabilisation leading to IL-1β release is distinct from the unconventional secretory mechanism employed by its structural homologues fibroblast growth factor 2 (FGF2) or IL-1α, a process that involves the formation of membrane pores but does not result in cell death. These discoveries reveal key processes at the initiation of an inflammatory response and deliver new insights into the mechanisms of protein release.
authors: Grupo de Inflamación Molecular, 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 (IMIB-Arrixaca), Murcia, Spain.
authors: F
authors: F
authors: Martín-Sánchez
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.|Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Singapore.
authors: C
authors: C
authors: Diamond
authors: Heidelberg University Biochemistry Center, Heidelberg, Germany.
authors: M
authors: M
authors: Zeitler
authors: Grupo de Inflamación Molecular, 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 (IMIB-Arrixaca), Murcia, Spain.
authors: A I
authors: AI
authors: Gomez
authors: Grupo de Inflamación Molecular, 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 (IMIB-Arrixaca), Murcia, Spain.
authors: A
authors: A
authors: Baroja-Mazo
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: J
authors: J
authors: Bagnall
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: D
authors: D
authors: Spiller
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: M
authors: M
authors: White
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: M J D
authors: MJ
authors: Daniels
authors: Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Singapore.
authors: A
authors: A
authors: Mortellaro
authors: Probelte Biotechnology, S.L., Murcia, Spain.
authors: M
authors: M
authors: Peñalver
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: P
authors: P
authors: Paszek
authors: Heidelberg University Biochemistry Center, Heidelberg, Germany.
authors: J P
authors: JP
authors: Steringer
authors: Heidelberg University Biochemistry Center, Heidelberg, Germany.
authors: W
authors: W
authors: Nickel
authors: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: D
authors: D
authors: Brough
authors: Grupo de Inflamación Molecular, 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 (IMIB-Arrixaca), Murcia, Spain.|Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors: P
authors: P
authors: Pelegrín
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008081:Liposomes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D010539:Permeability / Q000187:drug effects; D011188:Potassium / Q000032:analysis / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D047348:Hydrolyzable Tannins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008081:Liposomes; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; C115642:punicalagin; D000255:Adenosine Triphosphate; D020170:Caspase 1; D011188:Potassium