Quantitative H2S-mediated protein sulfhydration reveals metabolic reprogramming during the integrated stress response

Gao, Xing; Krokowski, Dawid; Guan, Bo; Bederman, Ilya; Majumder, Mithu; Parisien, Marc; Diatchenko, Luda; Kabil, Ömer; Willard, Belinda; Banerjee, Ruma; Wang, Benlian; Bebek, Gürkan; Evans, Charles R.; Fox, Paul L.; Gerson, Stanton L.; Hoppel, Charles L.; Liu, Ming; Arvan, Peter; Hatzoglou, Maria

doi:10.7554/elife.10067

Cited by 174 publications

(250 citation statements)

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“…To validate transfer of the sulfane sulfur from TSTD1 to thioredoxin, the biotin thiol assay (BTA) was used. This assay distinguishes between persulfides and other oxidative cysteine modifications such as sulfenic acid (37). For this, wild-type thioredoxin and two cysteine mutants, i.e.…”

Section: Resultsmentioning

confidence: 99%

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Thiosulfate sulfurtransferase-like domain–containing 1 protein interacts with thioredoxin

Libiad

Motl

Akey

et al. 2018

Journal of Biological Chemistry

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ǂ These authors contributed equally to this work Rhodanese domains are structural modules present in the sulfurtransferase superfamily. These domains can exist as single units, in tandem repeats or fused to domains with other activities. Despite their prevalence across species, the specific physiological roles of most sulfurtransferases are not known. Mammalian rhodanese and mercaptopyruvate sulfurtransferase are perhaps the best-studied members of this protein superfamily and are involved in hydrogen sulfide metabolism. The relatively unstudied human thiosulfate sulfurtransferase like domain-containing 1 (TSTD1) protein, a single-domain cytoplasmic sulfurtransferase, was also postulated to play a role in the sulfide oxidation pathway using thiosulfate to form glutathione persulfide, for subsequent processing in the mitochondrial matrix. Prior kinetic analysis of TSTD1 was performed at pH 9.2, raising questions about relevance and the proposed model for TSTD1 function. In this study, we report a 1.04 Å resolution crystal structure of human TSTD1, which displays an exposed active site that is distinct from that of rhodanese and mercaptopyruvate sulfurtransferase. Kinetic studies with a combination of sulfur donors and acceptors reveal that TSTD1 exhibits a low K M for thioredoxin as a sulfane sulfur acceptor and that it utilizes thiosulfate inefficiently as a sulfur donor. The active site exposure and its interaction with thioredoxin, suggest that TSTD1 might play a role in sulfide-based signaling. The apical localization of TSTD1 in human colonic crypts, which interfaces with sulfide-releasing microbes, and the overexpression of TSTD1 in colon cancer, provides potentially intriguing clues as to its role in sulfide metabolism. Hydrogen sulfide (H 2 S)1 is an important signaling molecule with effects on multiple physiological processes including neuromodulation, inflammation and cardiac function (1-7). Maintaining healthy levels of H 2 S in mammalian cells requires tight control of its biosynthesis and its catabolism (8,9). H 2 S is produced endogenously by two enzymes in the transsulfuration pathway, cystathionine β-synthase and γ-cystathionase as well as by mercaptopyruvate sulfurtransferase (MST) (10-13). H 2 S is oxidized via the sulfide oxidation pathway to generate the end-products thiosulfate Protein persulfidation, a posttranslational modification of cysteine residues, is postulated to be a major mechanism by which H 2 S signals (17). However, the mechanism by which target proteins acquire this modification and the sulfur source(s) used in persulfidation reactions are unclear (18). Sulfurtransferases like rhodanese or the single rhodanese domain containing TSTD1 could potentially play a role in protein persulfidation because of their capacity to form an active site cysteine persulfide during their reaction cycle (18).The rhodanese superfamily members are distinguished by a structural module with an α/β topology in which α-helices surround a central five-stranded β-sheet core (19). At least three variations...

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Section: Resultsmentioning

confidence: 99%

“…Persulfide analysis on thioredoxin using the BTA assay-Persulfide transfer from TSTD1 to thioredoxin was assessed using a modified BTA as described previously (37). Briefly, 120 µg of TSTD1 was pre-incubated with 10 mM thiosulfate for 5 min in 1 mL 100 mM HEPES buffer, pH 7.4, at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Thiosulfate sulfurtransferase-like domain–containing 1 protein interacts with thioredoxin

Libiad

Motl

Akey

et al. 2018

Journal of Biological Chemistry

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“…In mammalian cells, a small but significant fraction of the proteome is persulfidated as a result of the endogenous production of H 2 S by enzymes of the transsulfuration pathway, which potentially results in significant metabolic changes in the cell (18). The extent to which such intramolecular signaling by RSS and shifts in metabolism are operative in bacteria is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Emerging evidence suggests that highly oxidized sulfur species, termed reactive sulfur species (RSS), are the actual sulfide-signaling species (13-16). These include HS•, cysteine sulfenic acids, cysteine persulfides, glutathione persulfides (GSSHs), and inorganic polysulfide species, which catalyze persulfidation of specific proteins and enzymes (13,(17)(18)(19)(20), although the functional impact of this protein modification is as yet not generally clear (17).Hydrogen sulfide inhibits respiration by poisoning cytochrome oxidase and binding and precipitating biologically required divalent transition metals, and is thus toxic at high concentrations (21). The ability to adapt to a sulfide-rich environment is therefore critical for the survival for some microorganisms.…”

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confidence: 99%

Sulfide-responsive transcriptional repressor SqrR functions as a master regulator of sulfide-dependent photosynthesis

Shimizu

Shen

Fang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

113

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Sulfide was used as an electron donor early in the evolution of photosynthesis, with many extant photosynthetic bacteria still capable of using sulfur compounds such as hydrogen sulfide (H 2 S) as a photosynthetic electron donor. Although enzymes involved in H 2 S oxidation have been characterized, mechanisms of regulation of sulfide-dependent photosynthesis have not been elucidated. In this study, we have identified a sulfide-responsive transcriptional repressor, SqrR, that functions as a master regulator of sulfide-dependent gene expression in the purple photosynthetic bacterium Rhodobacter capsulatus. SqrR has three cysteine residues, two of which, C41 and C107, are conserved in SqrR homologs from other bacteria. Analysis with liquid chromatography coupled with an electrospray-interface tandem-mass spectrometer reveals that SqrR forms an intramolecular tetrasulfide bond between C41 and C107 when incubated with the sulfur donor glutathione persulfide. SqrR is oxidized in sulfidestressed cells, and tetrasulfide-cross-linked SqrR binds more weakly to a target promoter relative to unmodified SqrR. C41S and C107S R. capsulatus SqrRs lack the ability to respond to sulfide, and constitutively repress target gene expression in cells. These results establish that SqrR is a sensor of H 2 S-derived reactive sulfur species that maintain sulfide homeostasis in this photosynthetic bacterium and reveal the mechanism of sulfide-dependent transcriptional derepression of genes involved in sulfide metabolism.sulfide sensor | photosynthesis regulation | reactive sulfur species | purple bacteria | Rhodobacter T he discovery of ∼550 deep-sea hydrothermal vents more than 30 y ago (1) has led to the theory that energy metabolism in early ancestral organisms may have arisen from deep-sea hydrothermal vents where simple inorganic molecules such as hydrogen sulfide or hydrogen gas, as well as methane, exist (2-4). Such ancient energy metabolism has been assumed to be similar to that of extant chemolithotrophs, which obtain energy from these molecules. Indeed, various chemolithoautotrophic microbes thrive in deep-sea hydrothermal vents and are capable of oxidizing sulfides, methane, and/or hydrogen gas for use as energy sources and electron donors (5). Some photosynthetic bacteria have also been isolated from deep-sea hydrothermal vents that can grow photosynthetically using sulfide as an electron donor and geothermal radiation as an energy source instead of solar radiation (6), as hypothesized for ancestral phototrophs.Many purple photosynthetic bacteria have remarkable metabolic versatility required to meet the energy demands of sulfidedependent and -independent photosynthesis as well as aerobic and anaerobic respiration. These bacteria tightly control the synthesis of their electron transfer proteins involved in each growth mode in response to a specific electron donor, oxygen tension, and light intensity (7, 8). Among these regulatory systems, oxygen-and lightsensing mechanisms have been well-studied; however, mechanisms used to sen...

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“…The transsulfuration pathway is regulated in response to various conditions such as oxidative stress (8,9) and insulin signaling (10,11). Furthermore, growing evidence indicates cross-talk between the endoplasmic reticulum (ER) stress response and the transsulfuration pathway (12,13). However, the mechanism by which the transsulfuration pathway switches to H 2 S production is not known.…”

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Heme-dependent Metabolite Switching Regulates H2S Synthesis in Response to Endoplasmic Reticulum (ER) Stress

Kabil

Yadav

Banerjee

2016

Journal of Biological Chemistry

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Substrate ambiguity and relaxed reaction specificity underlie the diversity of reactions catalyzed by the transsulfuration pathway enzymes, cystathionine ␤-synthase (CBS) and ␥-cystathionase (CSE). These enzymes either commit sulfur metabolism to cysteine synthesis from homocysteine or utilize cysteine and/or homocysteine for synthesis of H 2 S, a signaling molecule. We demonstrate that a kinetically controlled heme-dependent metabolite switch in CBS regulates these competing reactions where by cystathionine, the product of CBS, inhibits H 2 S synthesis by the second enzyme, CSE. Under endoplasmic reticulum stress conditions, induction of CSE and up-regulation of the CBS inhibitor, CO, a product of heme oxygenase-1, flip the operating preference of CSE from cystathionine to cysteine, transiently stimulating H 2 S production. In contrast, genetic deficiency of CBS leads to chronic stimulation of H 2 S production. This metabolite switch from cystathionine to cysteine and/or homocysteine renders H 2 S synthesis by CSE responsive to the known modulators of CBS: S-adenosylmethionine, NO, and CO. Used acutely, it regulates H 2 S synthesis; used chronically, it might contribute to disease pathology.

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Quantitative H2S-mediated protein sulfhydration reveals metabolic reprogramming during the integrated stress response

Cited by 174 publications

References 43 publications

Thiosulfate sulfurtransferase-like domain–containing 1 protein interacts with thioredoxin

Thiosulfate sulfurtransferase-like domain–containing 1 protein interacts with thioredoxin

Sulfide-responsive transcriptional repressor SqrR functions as a master regulator of sulfide-dependent photosynthesis

Heme-dependent Metabolite Switching Regulates H2S Synthesis in Response to Endoplasmic Reticulum (ER) Stress

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