Thioredoxin-interacting Protein (Txnip) Is a Feedback Regulator of S-Nitrosylation

• Published in: The Journal of biological chemistry Vol. 284; no. 52; pp. 36160 - 36166
• Main Authors: Forrester, Michael T., Seth, Divya, Hausladen, Alfred, Eyler, Christine E., Foster, Matthew W., Matsumoto, Akio, Benhar, Moran, Marshall, Harvey E., Stamler, Jonathan S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.12.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Cell Survival - physiology; Humans; Nitric Oxide - genetics; Nitric Oxide - metabolism; Oxidation-Reduction; Oxidative Stress - physiology; Protein Synthesis, Post-Translational Modification, and Degradation; Thioredoxin-Disulfide Reductase - antagonists & inhibitors; Thioredoxin-Disulfide Reductase - genetics; Thioredoxin-Disulfide Reductase - metabolism; Thioredoxins - genetics; Thioredoxins - metabolism
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M109.057729

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.