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Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function

Benjamin Jenkins, Yasmin Jenkins, Fernando Ponce Garcia Orcid Logo, Chloe Moscrop Orcid Logo, Iain Perry Orcid Logo, Matthew Hitchings Orcid Logo, Alejandro H. Uribe, Federico Bernuzzi, Simon Eastham Orcid Logo, James Cronin Orcid Logo, Ardena Berisha, Alexandra Howell, Joanne Davies, Julianna Blagih, Marta Williams, Morgan Marsden, Douglas J. Veale Orcid Logo, Luke Davies Orcid Logo, Micah Niphakis, David K. Finlay Orcid Logo, Linda V. Sinclair Orcid Logo, Benjamin F. Cravatt Orcid Logo, Andrew E. Hogan Orcid Logo, James A. Nathan Orcid Logo, Ian R. Humphreys Orcid Logo, Ursula Fearon, David Sumpton, Johan Vande Voorde Orcid Logo, Goncalo Dias do Vale Orcid Logo, Jeffrey G. McDonald Orcid Logo, Gareth W. Jones Orcid Logo, James A. Pearson Orcid Logo, Emma E. Vincent Orcid Logo, Nick Jones Orcid Logo

Nature Communications, Volume: 16, Issue: 1

Swansea University Authors: Benjamin Jenkins, Yasmin Jenkins, Fernando Ponce Garcia Orcid Logo, Iain Perry Orcid Logo, Matthew Hitchings Orcid Logo, James Cronin Orcid Logo, Luke Davies Orcid Logo, Nick Jones Orcid Logo

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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...

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Published in: Nature Communications
ISSN: 2041-1723
Published: Springer Science and Business Media LLC 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa70822
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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.</abstract><type>Journal Article</type><journal>Nature Communications</journal><volume>16</volume><journalNumber>1</journalNumber><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2041-1723</issnElectronic><keywords/><publishedDay>3</publishedDay><publishedMonth>11</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-11-03</publishedDate><doi>10.1038/s41467-025-65417-4</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>External research funder(s) paid the OA fee (includes OA grants disbursed by the Library)</apcterm><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&#x2014;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).</funders><projectreference/><lastEdited>2025-11-13T11:02:15.6037150</lastEdited><Created>2025-11-03T13:30:15.2177144</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Benjamin</firstname><surname>Jenkins</surname><order>1</order></author><author><firstname>Yasmin</firstname><surname>Jenkins</surname><order>2</order></author><author><firstname>Fernando</firstname><surname>Ponce Garcia</surname><orcid>0000-0003-0651-2704</orcid><order>3</order></author><author><firstname>Chloe</firstname><surname>Moscrop</surname><orcid>0009-0008-7419-8247</orcid><order>4</order></author><author><firstname>Iain</firstname><surname>Perry</surname><orcid>0000-0001-8530-4086</orcid><order>5</order></author><author><firstname>Matthew</firstname><surname>Hitchings</surname><orcid>0000-0002-5527-4709</orcid><order>6</order></author><author><firstname>Alejandro H.</firstname><surname>Uribe</surname><order>7</order></author><author><firstname>Federico</firstname><surname>Bernuzzi</surname><order>8</order></author><author><firstname>Simon</firstname><surname>Eastham</surname><orcid>0009-0005-3316-310x</orcid><order>9</order></author><author><firstname>James</firstname><surname>Cronin</surname><orcid>0000-0002-0590-9462</orcid><order>10</order></author><author><firstname>Ardena</firstname><surname>Berisha</surname><order>11</order></author><author><firstname>Alexandra</firstname><surname>Howell</surname><order>12</order></author><author><firstname>Joanne</firstname><surname>Davies</surname><order>13</order></author><author><firstname>Julianna</firstname><surname>Blagih</surname><order>14</order></author><author><firstname>Marta</firstname><surname>Williams</surname><order>15</order></author><author><firstname>Morgan</firstname><surname>Marsden</surname><order>16</order></author><author><firstname>Douglas J.</firstname><surname>Veale</surname><orcid>0000-0003-2802-4971</orcid><order>17</order></author><author><firstname>Luke</firstname><surname>Davies</surname><orcid>0000-0001-7767-4060</orcid><order>18</order></author><author><firstname>Micah</firstname><surname>Niphakis</surname><order>19</order></author><author><firstname>David K.</firstname><surname>Finlay</surname><orcid>0000-0003-2716-6679</orcid><order>20</order></author><author><firstname>Linda V.</firstname><surname>Sinclair</surname><orcid>0000-0003-1248-7189</orcid><order>21</order></author><author><firstname>Benjamin F.</firstname><surname>Cravatt</surname><orcid>0000-0001-5330-3492</orcid><order>22</order></author><author><firstname>Andrew E.</firstname><surname>Hogan</surname><orcid>0000-0001-5875-230x</orcid><order>23</order></author><author><firstname>James A.</firstname><surname>Nathan</surname><orcid>0000-0002-0248-1632</orcid><order>24</order></author><author><firstname>Ian R.</firstname><surname>Humphreys</surname><orcid>0000-0002-9512-5337</orcid><order>25</order></author><author><firstname>Ursula</firstname><surname>Fearon</surname><order>26</order></author><author><firstname>David</firstname><surname>Sumpton</surname><order>27</order></author><author><firstname>Johan Vande</firstname><surname>Voorde</surname><orcid>0000-0002-7686-0926</orcid><order>28</order></author><author><firstname>Goncalo Dias do</firstname><surname>Vale</surname><orcid>0000-0003-1104-0289</orcid><order>29</order></author><author><firstname>Jeffrey G.</firstname><surname>McDonald</surname><orcid>0000-0003-1570-4142</orcid><order>30</order></author><author><firstname>Gareth W.</firstname><surname>Jones</surname><orcid>0000-0002-0125-4841</orcid><order>31</order></author><author><firstname>James A.</firstname><surname>Pearson</surname><orcid>0000-0002-2867-2269</orcid><order>32</order></author><author><firstname>Emma E.</firstname><surname>Vincent</surname><orcid>0000-0002-8917-7384</orcid><order>33</order></author><author><firstname>Nick</firstname><surname>Jones</surname><orcid>0000-0003-4846-5117</orcid><order>34</order></author></authors><documents><document><filename>70822__35614__c5efb248218945a2b50483b82d44cd0d.pdf</filename><originalFilename>70822.VoR.pdf</originalFilename><uploaded>2025-11-13T11:00:23.3047366</uploaded><type>Output</type><contentLength>2143889</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>&#xA9; The Author(s) 2025. 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spelling 2025-11-13T11:02:15.6037150 v2 70822 2025-11-03 Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function 90f7cfd66781feba615436189178a528 Benjamin Jenkins Benjamin Jenkins true false b274a45a4bc6afb86b4111ad27f544d5 Yasmin Jenkins Yasmin Jenkins true false 255a64f4bf43b5a1e83000de40e9f41c 0000-0003-0651-2704 Fernando Ponce Garcia Fernando Ponce Garcia true false 7d630cc1fa34fdcd873711c80a874322 0000-0001-8530-4086 Iain Perry Iain Perry true false be98847c72c14a731c4a6b7bc02b3bcf 0000-0002-5527-4709 Matthew Hitchings Matthew Hitchings true false 9cfd17551c0d1f7438895121e4fbb6e8 0000-0002-0590-9462 James Cronin James Cronin true false ff080296775381560053d5e3a6e81745 0000-0001-7767-4060 Luke Davies Luke Davies true false 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false 2025-11-03 MEDS 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. Journal Article Nature Communications 16 1 Springer Science and Business Media LLC 2041-1723 3 11 2025 2025-11-03 10.1038/s41467-025-65417-4 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) 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). 2025-11-13T11:02:15.6037150 2025-11-03T13:30:15.2177144 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Benjamin Jenkins 1 Yasmin Jenkins 2 Fernando Ponce Garcia 0000-0003-0651-2704 3 Chloe Moscrop 0009-0008-7419-8247 4 Iain Perry 0000-0001-8530-4086 5 Matthew Hitchings 0000-0002-5527-4709 6 Alejandro H. Uribe 7 Federico Bernuzzi 8 Simon Eastham 0009-0005-3316-310x 9 James Cronin 0000-0002-0590-9462 10 Ardena Berisha 11 Alexandra Howell 12 Joanne Davies 13 Julianna Blagih 14 Marta Williams 15 Morgan Marsden 16 Douglas J. Veale 0000-0003-2802-4971 17 Luke Davies 0000-0001-7767-4060 18 Micah Niphakis 19 David K. Finlay 0000-0003-2716-6679 20 Linda V. Sinclair 0000-0003-1248-7189 21 Benjamin F. Cravatt 0000-0001-5330-3492 22 Andrew E. Hogan 0000-0001-5875-230x 23 James A. Nathan 0000-0002-0248-1632 24 Ian R. Humphreys 0000-0002-9512-5337 25 Ursula Fearon 26 David Sumpton 27 Johan Vande Voorde 0000-0002-7686-0926 28 Goncalo Dias do Vale 0000-0003-1104-0289 29 Jeffrey G. McDonald 0000-0003-1570-4142 30 Gareth W. Jones 0000-0002-0125-4841 31 James A. Pearson 0000-0002-2867-2269 32 Emma E. Vincent 0000-0002-8917-7384 33 Nick Jones 0000-0003-4846-5117 34 70822__35614__c5efb248218945a2b50483b82d44cd0d.pdf 70822.VoR.pdf 2025-11-13T11:00:23.3047366 Output 2143889 application/pdf Version of Record true © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/
title Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function
spellingShingle Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function
Benjamin Jenkins
Yasmin Jenkins
Fernando Ponce Garcia
Iain Perry
Matthew Hitchings
James Cronin
Luke Davies
Nick Jones
title_short Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function
title_full Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function
title_fullStr Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function
title_full_unstemmed Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function
title_sort Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function
author_id_str_mv 90f7cfd66781feba615436189178a528
b274a45a4bc6afb86b4111ad27f544d5
255a64f4bf43b5a1e83000de40e9f41c
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ff080296775381560053d5e3a6e81745
0fce0f7ddbdbfeb968f4e2f1e3f86744
author_id_fullname_str_mv 90f7cfd66781feba615436189178a528_***_Benjamin Jenkins
b274a45a4bc6afb86b4111ad27f544d5_***_Yasmin Jenkins
255a64f4bf43b5a1e83000de40e9f41c_***_Fernando Ponce Garcia
7d630cc1fa34fdcd873711c80a874322_***_Iain Perry
be98847c72c14a731c4a6b7bc02b3bcf_***_Matthew Hitchings
9cfd17551c0d1f7438895121e4fbb6e8_***_James Cronin
ff080296775381560053d5e3a6e81745_***_Luke Davies
0fce0f7ddbdbfeb968f4e2f1e3f86744_***_Nick Jones
author Benjamin Jenkins
Yasmin Jenkins
Fernando Ponce Garcia
Iain Perry
Matthew Hitchings
James Cronin
Luke Davies
Nick Jones
author2 Benjamin Jenkins
Yasmin Jenkins
Fernando Ponce Garcia
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
format Journal article
container_title Nature Communications
container_volume 16
container_issue 1
publishDate 2025
institution Swansea University
issn 2041-1723
doi_str_mv 10.1038/s41467-025-65417-4
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description 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.
published_date 2025-11-03T05:31:47Z
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score 11.089386

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