Published online before print December 21, 2006, doi: 10.1161/01.RES.0000256089.30318.20
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Submitted on July 17, 2006
Revised on November 16, 2006
Accepted on December 8, 2006
Glutathiolation Regulates Tumor Necrosis Factor-
-Induced Caspase-3 Cleavage and Apoptosis. Key Role for Glutaredoxin in the Death Pathway
Shi Pan * and Bradford C. Berk
From the Cardiovascular Research Institute and Department of Medicine, University of Rochester, NY.
* To whom correspondence should be addressed. E-mail: shi_pan{at}urmc.rochester.edu.
Caspase-3 cleavage and activation are known to play central roles in apoptosis. However, the mechanisms that regulate caspase-3 cleavage remain elusive. Glutaredoxin (Grx) is a ubiquitous redox molecule that is unique in its ability to regulate S-glutathiolation (glutathiolation) of proteins. Here we show the essential role of Grx in caspase-3 cleavage via regulation of caspase-3 glutathiolation. Grx activity was significantly upregulated by tumor necrosis factor-
in endothelial cells. Small interference RNA knock down of Grx significantly inhibited tumor necrosis factor--induced endothelial cell death due to attenuated caspase-3 cleavage concomitant with increased caspase-3 glutathiolation. Enhanced caspase-3 cleavage by wild-type Grx overexpression was reversed by catalytically inactive Grx (C22S), demonstrating a requirement for thioltransferase activity. Cysteine-to-serine mutations (C163S, C184S, and C220S) of caspase-3 that were predicted to prevent glutathiolation showed increased cleavage compared with wild-type caspase-3. This inverse correlation between caspase-3 glutathiolation and cleavage was further confirmed by the observation that in vitro glutathiolation of caspase-3 inhibited its cleavage with recombinant caspase-8. Furthermore, Grx association with caspase-3 was decreased by tumor necrosis factor-. These findings demonstrate a novel mechanism of caspase-3 regulation by Grx in tumor necrosis factor--induced apoptosis.
Key words: tumor necrosis factor • glutaredoxin • endothelial cell • caspase-3
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