UBE3A promotes foam cell formation and counters remyelination by targeting ABCA1 for proteasomal degradation

Melanie Loix, Sam Vanherle, Laura Bolkaerts, Sanne G. S. Verberk, Mattijs Punt, Flore Wouters, Brecht Moonen, Rob Verhagen, Suzanne A. E. Van Wouw, Aldo Jongejan, Ben Distel, Ype Elgersma, Mansour Haidar, Noam Zelcer, Jerome J. A. Hendriks and Jeroen F. J. Bogie ()
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Melanie Loix: Hasselt University
Sam Vanherle: Hasselt University
Laura Bolkaerts: Hasselt University
Sanne G. S. Verberk: Hasselt University
Mattijs Punt: Erasmus University Medical Center
Flore Wouters: Hasselt University
Brecht Moonen: Hasselt University
Rob Verhagen: Erasmus University Medical Center
Suzanne A. E. Van Wouw: University of Amsterdam
Aldo Jongejan: University of Amsterdam
Ben Distel: Erasmus University Medical Center
Ype Elgersma: Erasmus University Medical Center
Mansour Haidar: Hasselt University
Noam Zelcer: University of Amsterdam
Jerome J. A. Hendriks: Hasselt University
Jeroen F. J. Bogie: Hasselt University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62053-w

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