Journal article
Nedd8 regulates inflammasome-dependent caspase-1 activation
Molecular and cellular biology, Vol.35(3), pp.582-597
02/2015
Handle:
https://hdl.handle.net/2376/116069
PMCID: PMC4285429
PMID: 25452302
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 pro-caspase-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.
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Details
- Title
- Nedd8 regulates inflammasome-dependent caspase-1 activation
- Creators
- Jesus A Segovia - Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USASu-Yu Tsai - Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USATe-Hung Chang - Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USANiraj K Shil - Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington, USASusan T Weintraub - Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USAJohn D Short - Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USASantanu Bose - Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington, USA Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA sbose@vetmed.wsu.edu
- Publication Details
- Molecular and cellular biology, Vol.35(3), pp.582-597
- Academic Unit
- Veterinary Microbiology and Pathology, Department of
- Publisher
- United States
- Grant note
- P30 CA054174 / NCI NIH HHS P30 AG013319 / NIA NIH HHS DE14318 / NIDCR NIH HHS R01 AI083387 / NIAID NIH HHS T32 DE014318 / NIDCR NIH HHS 7P30CA54174-14 / NCI NIH HHS UL1 TR000149 / NCATS NIH HHS 8UL1 TR000149 / NCATS NIH HHS NIH-NIA P30AG013319 / NIA NIH HHS AI083387 / NIAID NIH HHS P01 AG019316 / NIA NIH HHS UL1 TR001120 / NCATS NIH HHS NIH-NIA P01AG19316 / NIA NIH HHS NIH-NCI P30 CA54174 / NCI NIH HHS
- Identifiers
- 99900548238701842
- Language
- English
- Resource Type
- Journal article