UBE3A promotes foam cell formation and counters remyelination by targeting ABCA1 for proteasomal degradation
The accumulation of foamy macrophages is a pathological hallmark of demyelinating brain disorders. Perturbed metabolism and efflux of intracellular lipids underlie the development of a harmful foamy macrophage phenotype in these disorders, yet, the molecular mechanisms underlying this dysregulation are poorly understood. Here, we show that the ubiquitin-proteasome system controls the turnover of the cholesterol efflux transporter ATP-binding cassette A1 (ABCA1) in lipid-loaded macrophages in the brain. We report that accumulation of myelin-derived lipids promotes the abundance and activity of ubiquitin-protein E3 ligase A (UBE3A) in macrophages, which stimulates ABCA1 ubiquitination and subsequent degradation. This boosts cellular lipid accumulation and induces an inflammatory macrophage phenotype that impairs remyelination. We further establish Tat-interacting protein 30 (TIP30), an inhibitor of importin β-mediated nuclear import, as an essential regulator of cytosolic UBE3A levels. Together, our findings identify UBE3A as a driver of foam cell formation and indicate that targeting UBE3A-mediated ABCA1 degradation is a promising strategy to enhance central nervous system repair.
Authors
- Aldo Jongejan (ORCID: https://orcid.org/0000-0002-8948-2549)
- Jeroen F. J. Bogie (ORCID: https://orcid.org/0000-0002-0016-1926)
- Sanne G. S. Verberk (ORCID: https://orcid.org/0000-0003-4509-4824)
- Ben Distel (ORCID: https://orcid.org/0000-0002-3046-205X)
- Mansour Haidar (ORCID: https://orcid.org/0000-0002-7838-007X)
- Jerome J. A. Hendriks (ORCID: https://orcid.org/0000-0002-7717-8582)
- Noam Zelcer (ORCID: https://orcid.org/0000-0001-6935-7532)
- Rob F. M. Verhagen (ORCID: https://orcid.org/0009-0005-0076-0151)
- Sam Vanherle (ORCID: https://orcid.org/0000-0001-5889-7058)
- Mattijs Punt
- Ype Elgersma (ORCID: https://orcid.org/0000-0002-3758-1297)
- Melanie Loix (ORCID: https://orcid.org/0000-0002-4107-6816)
- Suzanne A.E. van Wouw (ORCID: https://orcid.org/0000-0003-2508-2295)
- Flore Wouters
- Brecht Moonen
- Laura Bolkaerts (ORCID: https://orcid.org/0000-0002-6101-2748)
Institutions
- Erasmus MC (NL)
- Amsterdam University Medical Centers (NL)
- National MS Center Melsbroek
- Hasselt University (BE)
- University of Amsterdam (NL)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1038/s41467-025-62053-w
- Citations
- 3
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 5.45
Funders
- Angelman Syndrome Foundation
- Fonds Wetenschappelijk Onderzoek
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Universiteit Hasselt
- Vlaamse regering
- Bijzonder Onderzoeksfonds UGent