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Interleukin-1β Maturation Triggers Its Relocation to the Plasma Membrane for Gasdermin-D-Dependent and -Independent Secretion
- Source :
- Cell Reports, Vol 24, Iss 6, Pp 1425-1433 (2018), Cell Reports, vol. 24, no. 6, pp. 1425-1433
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Summary: 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. : 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. Keywords: interleukin-1, unconventional protein secretion, inflammasome, caspase-1, macrophage, neutrophil, gasdermin, pyroptosis, trafficking, phosphoinositides
- Subjects :
- 0301 basic medicine
medicine.medical_treatment
Interleukin-1beta
Caspase 1
Endogeny
Transfection
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
medicine
Humans
Secretion
lcsh:QH301-705.5
Unconventional protein secretion
Chemistry
Cell Membrane
Intracellular Signaling Peptides and Proteins
Pyroptosis
Interleukin
Inflammasome
Phosphate-Binding Proteins
Cell biology
caspase-1
gasdermin
inflammasome
interleukin-1
macrophage
neutrophil
phosphoinositides
pyroptosis
trafficking
unconventional protein secretion
030104 developmental biology
Cytokine
lcsh:Biology (General)
medicine.drug
Subjects
Details
- ISSN :
- 22111247
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....4bd0f4467b87a32af873789ac3b7a3a9