Interleukin-1β Maturation Triggers Its Relocation to the Plasma Membrane for Gasdermin-D-Dependent and -Independent Secretion

• Published in: Cell reports (Cambridge) Vol. 24; no. 6; pp. 1425 - 1433
• Main Authors: Monteleone, Mercedes, Stanley, Amanda C., Chen, Kaiwen W., Brown, Darren L., Bezbradica, Jelena S., von Pein, Jessica B., Holley, Caroline L., Boucher, Dave, Shakespear, Melanie R., Kapetanovic, Ronan, Rolfes, Verena, Sweet, Matthew J., Stow, Jennifer L., Schroder, Kate
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.08.2018; Elsevier
• Subjects: caspase-1; Cell Membrane - metabolism; gasdermin; Humans; Immunology; inflammasome; interleukin-1; Interleukin-1beta - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; macrophage; Microbiology and Parasitology; neutrophil; Phosphate-Binding Proteins - metabolism; phosphoinositides; pyroptosis; trafficking; Transfection; unconventional protein secretion; pyroptosis; unconventional protein secretion; interleukin-1; inflammasome; macrophage; gasdermin; caspase-1; neutrophil; trafficking; phosphoinositides
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.07.027

IL-1β requires processing by caspase-1 to generate the active, pro-inflammatory cytokine. Acute IL-1β secretion from inflammasome-activated macrophages requires caspase-1-dependent GSDMD cleavage, which also induces pyroptosis. Mechanisms of IL-1β secretion by pyroptotic and non-pyroptotic cells, and the precise functions of caspase-1 and GSDMD therein, are unresolved. Here, we show that, while efficient early secretion of endogenous IL-1β from primary non-pyroptotic myeloid cells in vitro requires GSDMD, later IL-1β release in vitro and in vivo proceeds independently of GSDMD. IL-1β maturation is sufficient for slow, caspase-1/GSDMD-independent secretion of ectopic IL-1β from resting, non-pyroptotic macrophages, but the speed of IL-1β release is boosted by inflammasome activation, via caspase-1 and GSDMD. IL-1β cleavage induces IL-1β enrichment at PIP2-enriched plasma membrane ruffles, and this is a prerequisite for IL-1β secretion and is mediated by a polybasic motif within the cytokine. We thus reveal a mechanism in which maturation-induced IL-1β trafficking facilitates its unconventional secretion. [Display omitted] •IL-1β cleavage by caspase-1 is both necessary and sufficient for IL-1β secretion•IL-1β maturation enables its relocation from the cytosol to the plasma membrane•Caspase-1 activity increases the speed of IL-1β secretion, via GSDMD•PIP2 membrane microdomains support GSDMD-dependent and -independent IL-1β exit Interleukin-1β is a potent pro-inflammatory cytokine whose dysregulated production drives a myriad of human diseases. Monteleone et al. uncover the trafficking mechanisms driving the unconventional secretion of mature interleukin-1β in non-pyroptotic and pyroptotic myeloid cells and reveal functions for caspase-1 and GSDMD therein.