Discovery of a redox-thiol switch regulating cellular energy metabolism

Gao, X.-H.; Li, L.; Parisien, M.; Mcleod, M.; Wu, J.; Bederman, I.; Gao, Z.; Krokowski, D.; Chirieleison, S. M.; Diatchenko, L.; Abbott, D.; Yee, V.; Hoppel, C.; Kibbey, R.; Holyoak, T.; Willard, B.; Arvan, P.; Hatzoglou, M.

doi:10.1101/520411

bioRxiv · 10.1101/520411

Discovery of a redox-thiol switch regulating cellular energy metabolism

Gao, X.-H.·Li, L.·Parisien, M.·Mcleod, M.·Wu, J.·Bederman, I.·Gao, Z.·Krokowski, D.·Chirieleison, S. M.·Diatchenko, L.·Abbott, D.·Yee, V.·Hoppel, C.·Kibbey, R.·Holyoak, T.·Willard, B.·Arvan, P.·Hatzoglou, M.

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Abstract

Previously, we reported that increased synthesis of the gas hydrogen sulfide (H2S) during the Integrated Stress Response (ISR) induced proteome-wide cysteine-sulfhydration with the predominant modified pathway being enzymes of cellular energy metabolism (Gao, et al. 2015). Using pancreatic beta cells and quantitative proteomics in this study, we identified a Redox Thiol Switch from S-glutathionylation to S-sulfhydration and we named it, RTSGS. About half of the identified proteins are involved in energy metabolism, and one novel target was the mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) whose catalytic Cys306was targeted by both modifications. The enzymatic activity of PCK2 was inhibited by S-glutathionylation, and this inhibition was largely reversed by S-sulfhydration. S-sulfhydration also reversed the S-glutathionylation-mediated inhibition of glucose flux, indicating a broad metabolic significance. We propose that a Redox Thiol Switch from S-glutathionylation to S-sulfhydration is a key mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.

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Gao, X.-H., Li, L., Parisien, M., Mcleod, M., Wu, J., Bederman, I., Gao, Z., Krokowski, D., Chirieleison, S. M., Diatchenko, L., Abbott, D., Yee, V., Hoppel, C., Kibbey, R., Holyoak, T., Willard, B., Arvan, P., Hatzoglou, M.. 2019-01-14. Discovery of a redox-thiol switch regulating cellular energy metabolism. https://doi.org/10.1101/520411

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