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Methylmercury directly modifies the 105th cysteine residue in oncostatin M to promote binding to tumor necrosis factor receptor 3 and inhibit cell growth

  • Molecular Toxicology
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Abstract

We previously found that methylmercury induces expression of oncostatin M (OSM), which is released extracellularly and binds to tumor necrosis factor receptor 3 (TNFR3), possibly enhancing its own toxicity. However, the mechanism by which methylmercury causes OSM to bind to TNFR3 rather than to its known receptors, OSM receptor and LIFR, is unknown. In this study, we aimed to elucidate the effect of methylmercury modification of cysteine residues in OSM on binding to TNFR3. Immunostaining of TNFR3-V5-expressing cells suggested that methylmercury promoted binding of OSM to TNFR3 on the cell membrane. In an in vitro binding assay, OSM directly bound to the extracellular domain of TNFR3, and this binding was promoted by methylmercury. Additionally, the formation of a disulfide bond in the OSM molecule was essential for the binding of both proteins, and LC/MS analysis revealed that methylmercury directly modified the 105th cysteine residue (Cys105) in OSM. Next, mutant OSM, in which Cys105 was replaced by serine or methionine, increased the binding to TNFR3, and a similar effect was observed in immunoprecipitation using cultured cells. Furthermore, cell proliferation was inhibited by treatment with Cys105 mutant OSMs compared with wildtype OSM, and this effect was cancelled by TNFR3 knockdown. In conclusion, we revealed a novel mechanism of methylmercury toxicity, in which methylmercury directly modifies Cys105 in OSM, thereby inhibiting cell proliferation via promoting binding to TNFR3. This indicates a chemical disruption in the interaction between the ligand and the receptor is a part of methylmercury toxicity.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was partially supported by Grants-in-Aid (JSPS KAKENHI Grant Number 15H05714 and 22H03752) for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Study of the Health Effects of Heavy Metals organized by the Ministry of the Environment of Japan. We thank Mitchell Arico from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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GWH, TN, AM and AN: designed the research. TT and GWH: wrote the manuscript. TT and JYL: prepared Fig. 1. SX and YK: prepared Figs. 2, 3 and 4. TH and SX: prepared Figs. 3 and 4. SX: prepared Fig. 4. TH: prepared Fig. 5. TT, TH and SX: prepared Fig. 6. All authors reviewed the manuscript.

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Correspondence to Gi-Wook Hwang.

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Toyama, T., Xu, S., Kanemitsu, Y. et al. Methylmercury directly modifies the 105th cysteine residue in oncostatin M to promote binding to tumor necrosis factor receptor 3 and inhibit cell growth. Arch Toxicol 97, 1887–1897 (2023). https://doi.org/10.1007/s00204-023-03520-5

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  • DOI: https://doi.org/10.1007/s00204-023-03520-5

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