TY - JOUR
T1 - PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis during ageing
AU - Danileviciute, Egle
AU - Zeng, Ni
AU - Capelle, Christophe M.
AU - Paczia, Nicole
AU - Gillespie, Mark A.
AU - Kurniawan, Henry
AU - Benzarti, Mohaned
AU - Merz, Myriam P.
AU - Coowar, Djalil
AU - Fritah, Sabrina
AU - Vogt Weisenhorn, Daniela Maria
AU - Gomez Giro, Gemma
AU - Grusdat, Melanie
AU - Baron, Alexandre
AU - Guerin, Coralie
AU - Franchina, Davide G.
AU - Léonard, Cathy
AU - Domingues, Olivia
AU - Delhalle, Sylvie
AU - Wurst, Wolfgang
AU - Turner, Jonathan D.
AU - Schwamborn, Jens Christian
AU - Meiser, Johannes
AU - Krüger, Rejko
AU - Ranish, Jeff
AU - Brenner, Dirk
AU - Linster, Carole L.
AU - Balling, Rudi
AU - Ollert, Markus
AU - Hefeng, Feng Q.
N1 - Funding Information:
This work was supported by the Luxembourg National Research Fund (FNR) CORE programme (CORE/14/BM/8231540/GeDES), the Luxembourg–RIKEN bilateral programme ‘TregBar’, ‘NEXTIMMUNE’ (PRIDE/11012546) and ‘CRiTiCS’ DTU (to F.Q.H.); individual Aide à la Formation Recherche grants to E.D. (PHD-2014-1/7603621) and N.Z. (PHD-2015-1/9989160); and other PhD position grants to C.M.C. (PRIDE/2015/10907093) and D.G.F. (through the Luxembourg–RIKEN bilateral programme (2015/11228353, ‘TregBar’)) through the group of F.Q.H. The work was also supported by the DFG (grant WU 164/5-1) to W.W. and by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network MitoPD (grant 031A430E to W.W. and D.M.V.W.). J.M. is supported by FNR ATTRACT (A18/BM/11809970). D.B. is supported by FNR ATTRACT (A14/BM/7632103) and FNR CORE grants (C21/BM/15796788 and C18/BM/12691266). R.K. is supported by the FNR NCER-PD and PEARL programme (FNR/P13/6682797). We also thank the Luxembourg Centre for Systems Biomedicine Metabolomics Platform for providing technical and analytical support and acknowledge the EMBL Genomics Core Facility (Heidelberg, V. Benes) for their microarray analysis. We thank A. Daujeumont, N. Ouzren, T. Li, O. Boyd, N. Bonjean, C. Davril, S. Köglsberger, J. Walter, X. Dong, S. Badeke and F. Fack for their expert technical support. We acknowledge M.P. Dufresne (Liege, Belgium) for allowing us to access their irradiator and N. Malvaus from the Luxembourg Red Cross for providing buffy coats and leukopaks.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/5
Y1 - 2022/5
N2 - 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 (Treg 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 Treg survival starting in young mice and reduces Treg 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 Treg 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 Treg homeostasis is dysregulated in many complex diseases, the DJ-1–PDHB axis represents a potential target to maintain or re-establish Treg homeostasis.
AB - 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 (Treg 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 Treg survival starting in young mice and reduces Treg 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 Treg 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 Treg homeostasis is dysregulated in many complex diseases, the DJ-1–PDHB axis represents a potential target to maintain or re-establish Treg homeostasis.
UR - http://www.scopus.com/inward/record.url?scp=85130736238&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/35618940
U2 - 10.1038/s42255-022-00576-y
DO - 10.1038/s42255-022-00576-y
M3 - Article
C2 - 35618940
AN - SCOPUS:85130736238
SN - 2522-5812
VL - 4
SP - 589
EP - 607
JO - Nature Metabolism
JF - Nature Metabolism
IS - 5
ER -