Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.

Glutarate is an intermediate of amino acid catabolism and an important metabolite for reprogramming T cell immunity. Glutarate exerts its effects either by directly inhibiting metabolite-dependent enzymes or through conjugation to substrates. Intriguingly, glutarylation can occur on protein and nonprotein substrates, but our understanding of these distinct glutaryl modifications is in its infancy. Here we uncover ABHD11 as a noncanonical deglutarylating enzyme critical for maintaining the tricarboxylic acid (TCA) cycle. Mechanistically, we find ABHD11 removes glutaryl adducts from lipoate-an essential fatty acid modification required for the TCA cycle. Loss of ABHD11 results in the accumulation of glutaryl-lipoyl adducts that drive an adaptive program, involving 2-oxoglutarate accumulation, that rewires mitochondrial metabolism. Functionally, this role of ABHD11 influences the metabolic programming of human CD8+ T cells. Therefore, our findings reveal lipoyl glutarylation as a reversible modification that regulates the TCA cycle.

Description

Acknowledgements: We thank all members of the Nathan and Johnson labs for their helpful comments on the work and manuscript. The authors gratefully acknowledge A. Checa and the Karolinska Institute Small-Molecule Mass Spectrometry Core Facility (KI-SMMS), supported by KI/SLL, for support in the sample analyses. We also gratefully acknowledge the support of the Cambridge Institute of Medical Research Mass Spectrometry Facility and the Flow Cytometry Facility of the School of Biological Sciences of the University of Cambridge. Bioenergetic experiments were performed at the Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK, with thanks to M. MacFarlane for access. This work was also supported by the NIHR BRC Flow Cytometry Facility. This study was supported by a Wellcome Senior Clinical Research Fellowship (215477/Z/19/Z to J.A.N.), a Wellcome Principal Research Fellowship (214283/Z/18/Z to R.S.J.) and a Lister Institute Research Fellowship (to J.A.N.). The work was also supported by an MRC (grant MR/X008118/1 to J.A.N.), a Wellcome Investigator award (222497/Z/21/Z to A.K.), a Leona M & Harry B Helmsley Charitable Trust award (R-2408-07256 to A.K.), the Ludwig Center at Harvard Medical School (to M.C.H.) and the Gene Lay Institute (to M.C.H.).

Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255

Funder: Leona M. and Harry B. Helmsley Charitable Trust (Helmsley Charitable Trust); doi: https://doi.org/10.13039/100007028

Keywords

Humans, Mitochondria, Citric Acid Cycle, Lipoylation, CD8-Positive T-Lymphocytes, Glutarates, T-Lymphocytes, Ketoglutaric Acids

Journal Title

Nat Chem Biol

Journal ISSN

1552-4450
1552-4469

Volume Title

21

Publisher

Springer Nature

Publisher DOI

https://doi.org/10.1038/s41589-025-01965-6

Rights and licensing

Except where otherwised noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/

Sponsorship

Wellcome Trust (215477/Z/19/Z)
Lister Institute of Preventive Medicine (unknown)
MRC (MR/X008118/1)
Wellcome Trust (214283/Z/18/Z)

Lister Institute Research Fellowship NIHR BRC Leona M & Harry B Helmsley Charitable Trust Ludwig Center at Harvard Medical School Gene Lay Institute

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