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

Cell Rep. 2018 Aug 7;24(6):1425-1433. 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.

Keywords: caspase-1; gasdermin; inflammasome; interleukin-1; macrophage; neutrophil; phosphoinositides; pyroptosis; trafficking; unconventional protein secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane / metabolism*
  • Humans
  • Interleukin-1beta / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Phosphate-Binding Proteins / metabolism*
  • Transfection


  • GSDMD protein, human
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Phosphate-Binding Proteins