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10.1128/MCB.00775-14

http://scihub22266oqcxt.onion/10.1128/MCB.00775-14
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C4285429!4285429!25452302
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suck abstract from ncbi


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pmid25452302      Mol+Cell+Biol 2015 ; 35 (3): 582-97
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  • Nedd8 Regulates Inflammasome-Dependent Caspase-1 Activation #MMPMID25452302
  • Segovia JA; Tsai SY; Chang TH; Shil NK; Weintraub ST; Short JD; Bose S
  • Mol Cell Biol 2015[Feb]; 35 (3): 582-97 PMID25452302show ga
  • Caspase-1 is activated by the inflammasome complex to process cytokines like interleukin-1? (IL-1?). 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-1? 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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