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

Rudolf Wedmann, Constantin Onderka, Shengwei Wei, István András Szijártó, Jan Lj Miljkovic, Aleksandra Mitrovic, Mike Lange, Sergey Savitsky, Pramod Kumar Yadav, Roberta Torregrossa, Ellen G. Harrer, Thomas Harrer, Isao Ishii, Maik Gollasch, Mark E. Wood, Erwan Galardon, Ming Xian, Matthew Whiteman, Ruma Banerjee, Milos R. Filipovic

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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.

Original languageEnglish
Pages (from-to)3414-3426
Number of pages13
JournalChemical Science
Volume7
Issue number5
DOIs
Publication statusPublished - 2016 Jan 1

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ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Wedmann, R., Onderka, C., Wei, S., Szijártó, I. A., Miljkovic, J. L., Mitrovic, A., Lange, M., Savitsky, S., Yadav, P. K., Torregrossa, R., Harrer, E. G., Harrer, T., Ishii, I., Gollasch, M., Wood, M. E., Galardon, E., Xian, M., Whiteman, M., Banerjee, R., & Filipovic, M. R. (2016). Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation. Chemical Science, 7(5), 3414-3426. https://doi.org/10.1039/c5sc04818d