RT Journal Article
SR Electronic
T1 Regulated Protein Denitrosylation by Cytosolic and Mitochondrial Thioredoxins
JF Science
JO Science
FD American Association for the Advancement of Science
SP 1050
OP 1054
DO 10.1126/science.1158265
VO 320
IS 5879
A1 Benhar, Moran
A1 Forrester, Michael T.
A1 Hess, Douglas T.
A1 Stamler, Jonathan S.
YR 2008
UL http://science.sciencemag.org/content/320/5879/1050.abstract
AB 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.