Glutathione supersulphide regulates T-cell receptor signalling

Sasaki, Y.; Numakura, T.; Yamada, M.; Sugiura, H.; Matsunaga, T.; Ida, T.; Morita, M.; Suzuki, A.; Matsumoto, S.; Kawaguchi, M.; Kawabe, T.; Tayama, S.; Okuyama, Y.; Takata, T.; Inaba, K.; Watanabe, S.; Suzuki, M.; Sano, H.; Kyogoku, Y.; Tanaka, R.; Mitsune, A.; Ichikawa, T.; Fujino, N.; Tamada, T.; Ishii, N.; Ichinose, M.; Akaike, T.; Motohashi, H.

doi:10.1101/2024.04.30.591985

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bioRxiv · 10.1101/2024.04.30.591985

Glutathione supersulphide regulates T-cell receptor signalling

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Abstract

Immunometabolism regulates functions and fates of immune cells including T cells. Supersulphides, which are universal metabolites containing catenated sulphur atoms, have various physiological functions based on their unique redox properties. Here we found that activation of T-cell receptor (TCR) signalling was accompanied by supersulphide decrease, which suggests a regulatory contribution of sulphur metabolism to immune function. Consistently, inhibiting supersulphide synthesis facilitated TCR activation and exacerbated allergen-induced type 2 inflammation in mice. Supplementation with glutathione trisulphide (GSSSG), a major endogenous supersulphide, suppressed TCR signalling in naive CD4+ T cells and their differentiation and effectively alleviated the inflammation. Docking simulation revealed interaction of GSSSG with CD3{varepsilon} chain in the TCR/CD3 complex, which was supported by mass spectrometry detection of persulphidated glutathionylation at a functionally important CXXC motif of CD3{varepsilon} chain. This study identified a new post-translational modification with supersulfides and demonstrated a critical contribution of sulphur metabolism to TCR signalling regulation.

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Sasaki, Y., Numakura, T., Yamada, M., Sugiura, H., Matsunaga, T., Ida, T., Morita, M., Suzuki, A., Matsumoto, S., Kawaguchi, M., Kawabe, T., Tayama, S., Okuyama, Y., Takata, T., Inaba, K., Watanabe, S., Suzuki, M., Sano, H., Kyogoku, Y., Tanaka, R., Mitsune, A., Ichikawa, T., Fujino, N., Tamada, T., Ishii, N., Ichinose, M., Akaike, T., Motohashi, H.. 2024-05-02. Glutathione supersulphide regulates T-cell receptor signalling. https://doi.org/10.1101/2024.04.30.591985

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