Article ; Online: Nedd8 regulates inflammasome-dependent caspase-1 activation.
Molecular and cellular biology
2014 Volume 35, Issue 3, Page(s) 582–597
Abstract: ... caspase-1 (and CARD) and Nedd8 suggested possible neddylation of caspase-1 CARD. Following inflammasome ... interaction of endogenous Nedd8 with caspase-1 CARD was detected in inflammasome-activated macrophages ... activation in primary macrophages, we observed colocalization of endogenous Nedd8 with caspase-1. Similarly ...
| 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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| MeSH term(s) | Animals ; Carrier Proteins ; Caspase 1/metabolism ; Enzyme Activation ; Humans ; Inflammasomes/metabolism ; Influenza A virus/isolation & purification ; Interleukin-1beta/biosynthesis ; Macrophages/metabolism ; Macrophages/virology ; Mice, Inbred C57BL ; NEDD8 Protein ; Ubiquitins/metabolism |
| Chemical Substances | Carrier Proteins ; Inflammasomes ; Interleukin-1beta ; NEDD8 Protein ; NEDD8 protein, human ; Nedd8 protein, mouse ; Ubiquitins ; Caspase 1 (EC 3.4.22.36) |
| Language | English |
| Publishing date | 2014-12-01 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 779397-2 |
| ISSN | 1098-5549 ; 0270-7306 |
| ISSN (online) | 1098-5549 |
| ISSN | 0270-7306 |
| DOI | 10.1128/MCB.00775-14 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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