[en] Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker regulating PDH activity in CD4(+) regulatory T cells (T(reg) cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs T(reg) survival starting in young mice and reduces T(reg) homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible T(reg) cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As T(reg) homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish T(reg) homeostasis.
Disciplines :
Neurology
Author, co-author :
Danileviciute, Egle
Zeng, Ni
Capelle, Christophe M.
Paczia, Nicole
Gillespie, Mark A.
Kurniawan, Henry ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
Benzarti, Mohaned
Merz, Myriam P.
Coowar, Djalil ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services
Fritah, Sabrina
Vogt Weisenhorn, Daniela Maria
Gomez Giro, Gemma ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
Grusdat, Melanie ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics
Baron, Alexandre ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Guerin, Coralie
Franchina, Davide G.
Léonard, Cathy
Domingues, Olivia
Delhalle, Sylvie
Wurst, Wolfgang
Turner, Jonathan ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC)
Schwamborn, Jens Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
Meiser, Johannes ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Krüger, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Ranish, Jeff
Brenner, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics
Linster, Carole ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Enzymology and Metabolism
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