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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Veröffentlicht in:	Nature communications Jg. 16; H. 1; S. 8077 - 18
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 29.08.2025 Nature Publishing Group Nature Portfolio
Schlagworte:	13/109 13/31 13/51 14/19 38/39 38/88 45/90 45/91 631/250/371 631/337/458/582 631/45/287/1197 631/45/612/1237 631/80/389/2023 64/60 82/80 96/21 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-Zugang:	Volltext
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-025-62053-w