Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation
Szijarto, Istvan Andras
Miljkovic, Jan Lj
Mitrović, Aleksandra D.
Yadav, Pramod Kumar
Harrer, Ellen G.
Wood, Mark E.
Filipovi, Milos R.
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Hydrogen sulfide (H2S) has emerged as a signalling molecule capable of regulating several important physiological functions such as blood pressure, neurotransmission and inflammation. The mechanisms behind these effects are still largely elusive and oxidative posttranslational modification of cysteine residues (protein persulfidation or S-sulfhydration) has been proposed as the main pathway for H2S-induced biological and pharmacological effects. As a signalling mechanism, persulfidation has to be controlled. Using an improved tag-switch assay for persulfide detection we show here that protein persulfide levels are controlled by the thioredoxin system. Recombinant thioredoxin showed an almost 10-fold higher reactivity towards cysteine persulfide than towards cystine and readily cleaved protein persulfides as well. This reaction resulted in H2S release suggesting that thioredoxin could be an important regulator of H2S levels from persulfide pools. Inhibition of the thioredoxin system cau...sed an increase in intracellular persulfides, highlighting thioredoxin as a major protein depersulfidase that controls H2S signalling. Finally, using plasma from HIV-1 patients that have higher circulatory levels of thioredoxin, we could prove depersulfidase role in vivo.
Извор:Chemical Science, 2016, 7, 5, 3414-3426
- Royal Soc Chemistry, Cambridge
- Medical Research Council [MR/M022706/1]
- French State in the frame of the Investments for the future Programme IdEx Bordeaux [ANR-10-IDEX-03-02]
- Deutsche Forschungsgemeinschaft
- Dr Werner Jackstadt-Stiftung
- American Heart Association [14POST18760003]
- Friedrich-Alexander University within the Emerging Field Initiative (MRIC)
- Brian Ridge Scholarship
- National Institutes of Health [HL58984, GM112455, NIH R01HL116571]