Histone deacetylase 7 mediates lipopolysaccharide-inducible mitochondrial fission in macrophages
Histone deacetylase 7 (HDAC7) drives several immunometabolism-related processes in macrophages including lipopolysaccharide (LPS)-inducible glycolysis and inflammatory mediator production. Using an advanced biotin ligase TurboID system in human macrophages, we report 104 candidate HDAC7 interaction partners that might contribute to its immunometabolic functions. One such protein is the mitochondrial fission-promoting GTPase dynamin-related protein 1 (DRP1, also known as DNM1L), which associates with HDAC7 in cells. Using gain- and loss-of-function genetic approaches, we show that HDAC7 promotes LPS-inducible mitochondrial fission in macrophages, as well as DRP1-dependent metabolic and inflammatory responses. HDAC7 enzymatic activity was dispensable for LPS-inducible fission, as previously reported for LPS-inducible glycolysis. However, a pharmacological inhibitor of HDAC7 attenuated fission in primary human and mouse macrophages, implicating its acetyl-lysine docking function in this response. HDAC7 thus drives inducible mitochondrial fission in macrophages. Small molecules targeting the acetyl-lysine docking function of HDAC7 might have applications in preventing pathological processes driven by dysregulated mitochondrial fission.
Authors
- Zherui Xiong (ORCID: https://orcid.org/0000-0002-5038-5629)
- Ronan Kapétanovic (ORCID: https://orcid.org/0000-0002-2908-1014)
- Kaustav Das Gupta (ORCID: https://orcid.org/0000-0001-6430-1660)
- Christian Engwerda (ORCID: https://orcid.org/0000-0003-2813-4804)
- Steven Zuryn (ORCID: https://orcid.org/0000-0002-3551-6790)
- Jessica A. Engel (ORCID: https://orcid.org/0000-0001-6175-1797)
- Robert C. Reid (ORCID: https://orcid.org/0000-0002-0829-239X)
- Matthew J. Sweet (ORCID: https://orcid.org/0000-0002-0406-8139)
- Robert G. Parton (ORCID: https://orcid.org/0000-0002-7494-5248)
- Kimberley S. Gunther (ORCID: https://orcid.org/0000-0002-2373-5064)
- Syeda Farhana Afroz (ORCID: https://orcid.org/0000-0001-6066-3445)
- James E. B. Curson (ORCID: https://orcid.org/0000-0002-4672-3357)
- Divya Ramnath (ORCID: https://orcid.org/0000-0002-1935-9043)
- David P. Fairlie (ORCID: https://orcid.org/0000-0002-7856-8566)
- Alun Jones (ORCID: https://orcid.org/0000-0002-9819-9163)
- Antje Blumenthal (ORCID: https://orcid.org/0000-0003-3673-7015)
- Jennifer H. Gunter (ORCID: https://orcid.org/0000-0003-2447-5732)
- Karoline D. Raven (ORCID: https://orcid.org/0000-0002-7579-9721)
- Rishika Abrol (ORCID: https://orcid.org/0000-0002-8541-0679)
Institutions
- Université de Tours (FR)
- Translational Research Institute (AU)
- Queensland University of Technology (AU)
- The University of Queensland (AU)
- QIMR Berghofer Medical Research Institute (AU)
- UCLA Medical Center (US)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- ARC Centre of Excellence for Innovations in Peptide and Protein Science (AU)
- Infectiologie et santé publique (FR)
Publication Details
- Journal
- Journal of Cell Science
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1242/jcs.264376
- Citations
- 2
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- University of Texas Southwestern Medical Center
- University of Queensland
- Medical Research Council
- National Health and Medical Research Council
- Queensland Brain Institute
- Monash Biomedicine Discovery Institute, Monash University