Inflammasome-dependent IL-1β release depends upon membrane permeabilisation.

Fatima Martín-Sánchez, Catherine Diamond, Marcel Zeitler, Ana Gomez-Sanchez, Alberto Baroja-Mazo, James Bagnall, David Spiller, Michael White, Michael Daniels, Alessandra Mortellaro, Marcos Peñalver, Pawel Paszek, Julia P. Steringer, Walter Nickel, David Brough, Pablo Pelegrin

    Research output: Contribution to journalArticlepeer-review


    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.Cell Death and Differentiation advance online publication, 12 February 2016; doi:10.1038/cdd.2015.176.
    Original languageEnglish
    Pages (from-to)1219-1231
    Number of pages13
    JournalCell Death & Differentiation
    Issue number7
    Early online date12 Feb 2016
    Publication statusPublished - Jul 2016

    Research Beacons, Institutes and Platforms

    • Dementia@Manchester


    Dive into the research topics of 'Inflammasome-dependent IL-1β release depends upon membrane permeabilisation.'. Together they form a unique fingerprint.

    Cite this