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Science 320 (5879): 1050-1054

Copyright © 2008 by the American Association for the Advancement of Science

Regulated Protein Denitrosylation by Cytosolic and Mitochondrial Thioredoxins

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

Abstract: 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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