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...

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Published in:Nature communications Vol. 16; no. 1; pp. 8077 - 18
Main Authors: Loix, Melanie, Vanherle, Sam, Bolkaerts, Laura, Verberk, Sanne G. S., Punt, Mattijs, Wouters, Flore, Moonen, Brecht, Verhagen, Rob, Van Wouw, Suzanne A. E., Jongejan, Aldo, Distel, Ben, Elgersma, Ype, Haidar, Mansour, Zelcer, Noam, Hendriks, Jerome J. A., Bogie, Jeroen F. J.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 29.08.2025
Nature Publishing Group
Nature Portfolio
Subjects:
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631/250/371
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631/45/287/1197
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631/80/389/2023
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ABCA1 protein
Accumulation
Animals
ATP Binding Cassette Transporter 1 - genetics
ATP Binding Cassette Transporter 1 - metabolism
ATP-binding protein
Bone marrow
Brain
Brain - metabolism
Central nervous system
Cholesterol
Degradation
Demyelination
Disorders
Efflux
Enzymes
Foam Cells - metabolism
Gene expression
Genotype & phenotype
Humanities and Social Sciences
Humans
Lipid metabolism
Lipids
Macrophages
Male
Metabolism
Metabolites
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular modelling
multidisciplinary
Myelin
Myelin Sheath - metabolism
Myelination
Nuclear transport
Phenotypes
Proteasome Endopeptidase Complex - metabolism
Proteasomes
Proteins
Proteolysis
Remyelination - physiology
Science
Science (multidisciplinary)
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Foamy macrophages are a pathological hallmark of demyelinating brain disorders. Here, the authors identify the molecular mechanisms underlying the faulty regulation of lipid efflux that cause accumulation, suggesting a promising strategy to enhance central nervous system repair.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-025-62053-w