PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis

Danileviciute, E.; Zeng, N.; Capelle, C.; Paczia, N.; Gillespie, M. A.; Kurniawan, H.; Coowar, D.; Vogt-Weisenhorn, D.; Gomez-Giro, G.; Grusdat, M.; Baron, A.; Guerin, C.; Franchina, D. G.; Leonard, C.; Domingues, O.; Delhalle, S.; Wurst, W.; Schwamborn, J. C.; Krueger, R.; Ranish, J.; Brenner, D.; Linster, C. L.; Balling, R.; Ollert, M.; He, F. Q.

doi:10.1101/2019.12.20.884809

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bioRxiv · 10.1101/2019.12.20.884809

PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis

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Abstract

Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme into the tricarboxylic acid (TCA) cycle. Here we show that PARK7/DJ-1, a key familial Parkinsons disease (PD) gene, is a pacemaker controlling PDH activity in CD4 regulatory T cells (Tregs). DJ-1 bound to PDH-E1 beta (PDHB), inhibiting the phosphorylation of PDH-E1 alpha (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Dj-1 depletion impaired Treg proliferation and cellularity maintenance in older mice, increasing the severity during the remission phase of experimental autoimmune encephalomyelitis (EAE). The compromised proliferation and differentiation of Tregs in Dj-1 knockout mice were caused via regulating PDH activity. These findings provide novel insight into the already complicated regulatory machinery of the PDH complex and demonstrate that the DJ-1-PDHB axis represents a potent target to maintain Treg homeostasis, which is dysregulated in many complex diseases.

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Danileviciute, E., Zeng, N., Capelle, C., Paczia, N., Gillespie, M. A., Kurniawan, H., Coowar, D., Vogt-Weisenhorn, D., Gomez-Giro, G., Grusdat, M., Baron, A., Guerin, C., Franchina, D. G., Leonard, C., Domingues, O., Delhalle, S., Wurst, W., Schwamborn, J. C., Krueger, R., Ranish, J., Brenner, D., Linster, C. L., Balling, R., Ollert, M., He, F. Q.. 2019-12-23. PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis. https://doi.org/10.1101/2019.12.20.884809

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