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Science 23 May 2008:
Vol. 320. no. 5879, pp. 1050 - 1054
DOI: 10.1126/science.1158265
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Research Articles

Regulated Protein Denitrosylation by Cytosolic and Mitochondrial Thioredoxins

Moran Benhar,1 Michael T. Forrester,2 Douglas T. Hess,1 Jonathan S. Stamler1,2*

Nitric oxide acts substantially in cellular signal transduction through stimulus-coupled S-nitrosylation of cysteine residues. The mechanisms that might subserve protein denitrosylation in cellular signaling remain uncharacterized. Our search for denitrosylase activities focused on caspase-3, an exemplar of stimulus-dependent denitrosylation, and identified thioredoxin and thioredoxin reductase in a biochemical screen. In resting human lymphocytes, thioredoxin-1 actively denitrosylated cytosolic caspase-3 and thereby maintained a low steady-state amount of S-nitrosylation. Upon stimulation of Fas, thioredoxin-2 mediated denitrosylation of mitochondria-associated caspase-3, a process required for caspase-3 activation, and promoted apoptosis. Inhibition of thioredoxin-thioredoxin reductases enabled identification of additional substrates subject to endogenous S-nitrosylation. Thus, specific enzymatic mechanisms may regulate basal and stimulus-induced denitrosylation in mammalian cells.

1 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
2 Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.

* To whom correspondence should be addressed. E-mail: staml001{at}mc.duke.edu

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