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Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function
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Chloe Moscrop ,
Iain Perry ,
Matthew Hitchings ,
Alejandro H. Uribe,
Federico Bernuzzi,
Simon Eastham ,
James Cronin ,
Ardena Berisha,
Alexandra Howell,
Joanne Davies,
Julianna Blagih,
Marta Williams,
Morgan Marsden,
Douglas J. Veale ,
Luke Davies ,
Micah Niphakis,
David K. Finlay ,
Linda V. Sinclair ,
Benjamin F. Cravatt ,
Andrew E. Hogan ,
James A. Nathan ,
Ian R. Humphreys ,
Ursula Fearon,
David Sumpton,
Johan Vande Voorde ,
Goncalo Dias do Vale ,
Jeffrey G. McDonald ,
Gareth W. Jones ,
James A. Pearson ,
Emma E. Vincent ,
Nick Jones
Nature Communications, Volume: 16, Issue: 1
Swansea University Authors:
Benjamin Jenkins, Yasmin Jenkins, Fernando Ponce Garcia , Iain Perry , Matthew Hitchings , James Cronin , Luke Davies , Nick Jones
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DOI (Published version): 10.1038/s41467-025-65417-4
Abstract
α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in...
| Published in: | Nature Communications |
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| ISSN: | 2041-1723 |
| Published: |
Springer Science and Business Media LLC
2025
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70822 |
| Abstract: |
α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T-cell metabolism and function is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T-cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using murine models of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T-cells and delays the onset of diabetes in vivo in female mice. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T-cell-mediated inflammation. |
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| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
Y.R.J. is funded by a Swansea University Research Excellence Scholarship. A.H.U., F.B. and D.S. are funded by Cancer Research UK core funding to the CRUK Scotland Institute. L.C.D. is funded by an MRC New Investigator Research Grant (MR/Y013816/1). J.A.N is supported by a Wellcome Senior Clinical Research Fellowship (215477/Z/19/Z). J.V.V. is supported by a Cancer Research UK—Career Development Fellowship (RCCCDF-Nov23/100001) and by a Lord Kelvin/Adam Smith (LKAS) Leadership Fellowship from the University of Glasgow. J.G.M. is funded by National Institutes for Health (NIH) research grants (UL1TR003163, 1P30DK127984 and P01HL160487). G.W.J. is funded by a Versus Arthritis Career Development Fellowship (20305). J.A.P is supported by an MRC Career Development Award (MR/T010525/1). E.E.V is supported by a Diabetes UK RD Lawrence Fellowship (17/0005587), an MRC Research Grant (MR/Z505651/1) and by Cancer Research UK (C18281/A29019). N.J. is supported by an MRC New Investigator Research Grant (MR/X000095/1). |
| Issue: |
1 |