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

2009; Elsevier BV; Volume: 284; Issue: 52 Linguagem: Inglês

10.1074/jbc.m109.057729

1083-351X

Michael T. Forrester, Divya Seth, Alfred Hausladen, Christine E. Eyler, Matthew W. Foster, Akio Matsumoto, Moran Benhar, Harvey E. Marshall, Jonathan S. Stamler,

Connexins and lens biology

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.