Thioredoxin-interacting protein (Txnip) is a feedback regulator of S-nitrosylation.
Nitric oxide exerts a plethora of biological effects via protein S-nitrosylation, a redox-based reaction that converts a protein Cys thiol to a S-nitrosothiol. However, although the regulation of protein S-nitrosylation has been the subject of extensive study, much less is known about the systems governing protein denitrosylation. Most recently, thioredoxin/thioredoxin reductases were shown to mediate both basal and stimulus-coupled protein denitrosylation. We now demonstrate that protein denitrosylation by thioredoxin is regulated dynamically by thioredoxin-interacting protein (Txnip), a thioredoxin inhibitor. Endogenously synthesized nitric oxide represses Txnip, thereby facilitating thioredoxin-mediated denitrosylation. Autoregulation of denitrosylation thus allows cells to survive nitrosative stress. Our findings reveal that denitrosylation of proteins is dynamically regulated, establish a physiological role for thioredoxin in protection from nitrosative stress, and suggest new approaches to manipulate cellular S-nitrosylation.
Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710; Medical Scientist Training Program, Duke University Medical Center, Durham, North Carolina 27710.
Michael T
MT
Forrester
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Divya
D
Seth
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Alfred
A
Hausladen
Medical Scientist Training Program, Duke University Medical Center, Durham, North Carolina 27710; Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710.
Christine E
CE
Eyler
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Matthew W
MW
Foster
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Akio
A
Matsumoto
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Moran
M
Benhar
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Harvey E
HE
Marshall
Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710. Electronic address: staml001@mc.duke.edu.
Jonathan S
JS
Stamler
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; C486715:TXNIP protein, human; D009569:Nitric Oxide; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase