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Chem Sci. 2016 May 25;7(5):3414-3426. Epub 2016 Feb 19.

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

Author information

1
Department of Chemistry and Pharmacy , Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen , Germany . Email: milos.filipovic@ibgc.cnrs.fr.
2
Charité Campus Virchow , Nephrology/Intensive Care , Berlin , Germany.
3
Department of Chemistry , University of Belgrade , Belgrade , Serbia.
4
Department of Biological Chemistry , University of Michigan , Ann Arbor , USA.
5
University of Exeter Medical School , St. Luke's Campus , Exeter , UK ; Biosciences , College of Life and Environmental Sciences of Biosciences , University of Exeter , Streatham Campus , Exeter , Devon , UK.
6
Infectious Diseases Section , Department of Internal Medicine 3 , Universitätsklinikum Erlangen , Friedrich-Alexander-University, Erlangen-Nürnberg , Germany.
7
Department of Biochemistry , Graduate School of Pharmaceutical Sciences , Keio University , Tokyo , Japan.
8
Biosciences , College of Life and Environmental Sciences of Biosciences , University of Exeter , Streatham Campus , Exeter , Devon , UK.
9
UMR CNRS 8601 , Université Paris Descartes , Sorbonne Paris Cité , Paris , France.
10
Department of Chemistry , Washington State University , Pullman , USA.
11
University of Exeter Medical School , St. Luke's Campus , Exeter , UK.
12
Department of Chemistry and Pharmacy , Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen , Germany . Email: milos.filipovic@ibgc.cnrs.fr; Université de Bordeaux , IBGC , UMR 5095 , F-33077 Bordeaux , France ; CNRS , IBGC , UMR 5095 , F-33077 Bordeaux , France.

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.

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