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Issue 5, 2016
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Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation

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Abstract

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 caused 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.

Graphical abstract: Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation

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Supplementary files

Article information


Submitted
13 Dec 2015
Accepted
09 Feb 2016
First published
09 Feb 2016

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2016,7, 3414-3426
Article type
Edge Article

Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation

R. Wedmann, C. Onderka, S. Wei, I. A. Szijártó, J. Lj. Miljkovic, A. Mitrovic, M. Lange, S. Savitsky, P. K. Yadav, R. Torregrossa, E. G. Harrer, T. Harrer, I. Ishii, M. Gollasch, M. E. Wood, E. Galardon, M. Xian, M. Whiteman, R. Banerjee and M. R. Filipovic, Chem. Sci., 2016, 7, 3414
DOI: 10.1039/C5SC04818D

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