Research > Team Signaling by Gasotransmitters

Signaling by Gasotransmitters

Principal Investigator : Milos Filipovic


Team Members

Biljana Bursac - Post-Doc FRM

Milos Filipovic - CRCN CNRS

Stephanie Holst -

Emilia Kouroussis - Doctorante MESR

Dunja Petrovic - Doctorante FRM

Sonia Schott-Roux - IECN CNRS

Thibaut Vignane -


Research Activity

In the past few years we have been intensively working on elucidating the mechanisms by which hydrogen sulphide (H2S), commonly known as a substance that gives unpleasant smell to the rotten eggs, controls our body functions and could be used for therapeutic purposes. We demonstrated that H2S could react with peroxynitrite to prevent apoptosis and necrosis caused by this oxidant, we identified thionitrous acid (HSNO) as a new signaling molecule that could modulate protein cysteine residues and we even went one step further in clarifying the signaling effects of H2S and NO. We showed that blood pressure is regulated by the product of the reaction between NO and H2S, called nitroxyl (HNO), which modifies wasabi/mustard oil receptor known as TRPA1, and induces the release of the strongest known vasodilator, calcitonine gene-related peptide (Eberhardt et al, 2014).


A new oxidative posttranslational modification of cysteine (oxPTM) residues (protein persulfidation or S-sulfhydration, P-SSH) has been proposed as the main pathway for H2S-induced biological and pharmacological effects. As a signalling mechanism, persulfidation has to be controlled. Using a tag-switch assay, selectively designed for persulfide detection, we discovered that protein persulfide levels are controlled by the intracellular thioredoxin system (Wedman et al, 2016). Furthermore, the use of tag-switch helped us starting to unravel the mechanisms of protein persulfidation (Cuevasanta et al, 2015, Yadav et al, 2015).




We are currently trying to understand all the mechanisms of P-SSH formation/degradation and the actual place of this oxPTM when compared to the other oxPTM, such as S-nitrosation and S-sulfenylation, in order to gain high-resolution structural, functional, quantitative, and spatio-temporal information on their dynamics. Furthermore we work to understand how persulfidation affects the structure, function and (patho)physiological role of certain proteins important for the regulation of inflammation, autophagy, Huntington’s disease and suspended animation-like state.


External website of the team


Selected publications 2012-2018

Vitvitsky V, Miljkovic JL, Bostelaar T, Adhikari B, Yadav PK, Steiger AK, Torregrossa R, Pluth MD, Whiteman M, Banerjee R, Filipovic MR. Cytochrome c Reduction by H<sub>2</sub>S Potentiates Sulfide Signaling. ACS Chem Biol. 2018 Aug 17;13(8):2300-2307

Szijártó IA, Markó L, Filipovic MR, Miljkovic JL, Tabeling C, Tsvetkov D, Wang N, Rabelo LA, Witzenrath M, Diedrich A, Tank J, Akahoshi N, Kamata S, Ishii I, Gollasch M. Cystathionine ?-Lyase-Produced Hydrogen Sulfide Controls Endothelial NO Bioavailability and Blood Pressure. Hypertension. 2018 Jun;71(6):1210-1217

Filipovic MR, Zivanovic J, Alvarez B, Banerjee R. Chemical Biology of H<sub>2</sub>S Signaling through Persulfidation. Chem Rev. 2018 Feb 14;118(3):1253-1337

Filipovic MR, Jovanovic VM. More than just an intermediate: hydrogen sulfide signalling in plants. J Exp Bot. 2017 Oct 13;68(17):4733-4736

Oehler B, Kistner K, Martin C, Schiller J, Mayer R, Mohammadi M, Sauer RS, Filipovic MR, Nieto FR, Kloka J, Pflücke D, Hill K, Schaefer M, Malcangio M, Reeh PW, Brack A, Blum R, Rittner HL. Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation. Sci Rep. 2017 Jul 14;7(1):5447

Wedmann R, Ivanovic-Burmazovic I, Filipovic MR. Nitrosopersulfide (SSNO<sup>-</sup>) decomposes in the presence of sulfide, cyanide or glutathione to give HSNO/SNO<sup>-</sup>: consequences for the assumed role in cell signalling. Interface Focus. 2017 Apr 6;7(2):20160139

Ruetz M, Kumutima J, Lewis BE, Filipovic MR, Lehnert N, Stemmler TL, Banerjee R. A distal ligand mutes the interaction of hydrogen sulfide with human neuroglobin. J Biol Chem. 2017 Apr 21;292(16):6512-6528

Kenkel I, Franke A, Dürr M, Zahl A, Dücker-Benfer C, Langer J, Filipovi? MR, Yu M, Puchta R, Fiedler SR, Shores MP, Goldsmith CR, Ivanovi?-Burmazovi? I. Switching between Inner- and Outer-Sphere PCET Mechanisms of Small-Molecule Activation: Superoxide Dismutation and Oxygen/Superoxide Reduction Reactivity Deriving from the Same Manganese Complex. J Am Chem Soc. 2017 Feb 1;139(4):1472-1484

Jankovic A, Ferreri C, Filipovic M, Ivanovic-Burmazovic I, Stancic A, Otasevic V, Korac A, Buzadzic B, Korac B. Targeting the superoxide/nitric oxide ratio by L-arginine and SOD mimic in diabetic rat skin. Free Radic Res. 2016 Nov;50(sup1):S51-S63

Moparthi L, Kichko TI, Eberhardt M, Högestätt ED, Kjellbom P, Johanson U, Reeh PW, Leffler A, Filipovic MR, Zygmunt PM. Human TRPA1 is a heat sensor displaying intrinsic U-shaped thermosensitivity. Sci Rep. 2016 Jun 28;6:28763

Bostelaar T, Vitvitsky V, Kumutima J, Lewis BE, Yadav PK, Brunold TC, Filipovic M, Lehnert N, Stemmler TL, Banerjee R. Hydrogen Sulfide Oxidation by Myoglobin. J Am Chem Soc. 2016 Jul 13;138(27):8476-88

Wedmann R, Onderka C, Wei S, Szijártó IA, Miljkovic JL, Mitrovic A, Lange M, Savitsky S, Yadav PK, Torregrossa R, Harrer EG, Harrer T, Ishii I, Gollasch M, Wood ME, Galardon E, Xian M, Whiteman M, Banerjee R, Filipovic MR. Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation. Chem Sci. 2016 May 25;7(5):3414-3426

Cuevasanta E, Lange M, Bonanata J, Coitiño EL, Ferrer-Sueta G, Filipovic MR, Alvarez B. Reaction of Hydrogen Sulfide with Disulfide and Sulfenic Acid to Form the Strongly Nucleophilic Persulfide. J Biol Chem. 2015 Nov 6;290(45):26866-80

Eberhardt M, Dux M, Namer B, Miljkovic J, Cordasic N, Will C, Kichko TI, de la Roche J, Fischer M, Suárez SA, Bikiel D, Dorsch K, Leffler A, Babes A, Lampert A, Lennerz JK, Jacobi J, Martí MA, Doctorovich F, Högestätt ED, Zygmunt PM, Ivanovic-Burmazovic I, Messlinger K, Reeh P, Filipovic MR. H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signalling pathway. Nat Commun. 2014 Jul 15;5:4381

Zhang D, Macinkovic I, Devarie-Baez NO, Pan J, Park CM, Carroll KS, Filipovic MR, Xian M. Detection of protein S-sulfhydration by a tag-switch technique. Angew Chem Int Ed Engl. 2014 Jan 7;53(2):575-81

Miljkovic JLj, Kenkel I, Ivanovi?-Burmazovi? I, Filipovic MR. Generation of HNO and HSNO from nitrite by heme-iron-catalyzed metabolism with H?S. Angew Chem Int Ed Engl. 2013 Nov 11;52(46):12061-4

Filipovic MR, Miljkovic JLj, Nauser T, Royzen M, Klos K, Shubina T, Koppenol WH, Lippard SJ, Ivanovi?-Burmazovi? I. Chemical characterization of the smallest S-nitrosothiol, HSNO; cellular cross-talk of H2S and S-nitrosothiols. J Am Chem Soc. 2012 Jul 25;134(29):12016-27

Winocour E, Callaham MF, Huberman E. Perturbation of the cell cycle by adeno-associated virus. Virology. 1988 Dec;167(2):393-9