Nedd8 regulates inflammasome-dependent caspase-1 activation

Jesus A. Segovia, Su Yu Tsai, Te Hung Chang, Niraj K. Shil, Susan T. Weintraub, John D. Short, Santanu Bose

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Caspase-1 is activated by the inflammasome complex to process cytokines like interleukin-1β (IL-1β). Pro-caspase-1 consists of three domains, CARD, p20, and p10. Association of pro-caspase-1 with the inflammasome results in initiation of its autocatalytic activity, culminating in self-cleavage that generates catalytically active subunits (p10 and p20). In the current study, we show that Nedd8 is required for efficient self-cleavage of pro-caspase-1 to generate its catalytically active subunits. Nedd8 silencing or treating cells with the neddylation inhibitor MLN4924 led to diminished caspase-1 processing and reduced IL-1β maturation following inflammasome activation. Coimmunoprecipitation and mass spectrometric analysis of 293 cells overexpressing procaspase-1 (and CARD) and Nedd8 suggested possible neddylation of caspase-1 CARD. Following inflammasome activation in primary macrophages, we observed colocalization of endogenous Nedd8 with caspase-1. Similarly, interaction of endogenous Nedd8 with caspase-1 CARD was detected in inflammasome-activated macrophages. Furthermore, enhanced autocatalytic activity of pro-caspase-1 was observed following Nedd8 overexpression in 293 cells, and such activity in inflammasome-activated macrophages was drastically diminished upon treatment of cells with MLN4924. Thus, our studies demonstrate a role of Nedd8 in regulating caspase-1 activation following inflammasome activation, presumably via augmenting autoprocessing/cleavage of pro-caspase-1 into its corresponding catalytically active subunits.

Original languageEnglish (US)
Pages (from-to)582-597
Number of pages16
JournalMolecular and cellular biology
Volume35
Issue number3
DOIs
StatePublished - Jan 1 2015

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Segovia, J. A., Tsai, S. Y., Chang, T. H., Shil, N. K., Weintraub, S. T., Short, J. D., & Bose, S. (2015). Nedd8 regulates inflammasome-dependent caspase-1 activation. Molecular and cellular biology, 35(3), 582-597. https://doi.org/10.1128/MCB.00775-14