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

Abstract

Multiple sclerosis (MS) is a devastating neurological disease and one of the most prevalent autoimmune diseases in the Western world. Foamy macrophages loaded with myelin-derived lipids are a pathological hallmark of MS lesions. Emerging evidence indicates that perturbed metabolism and efflux of intracellular lipids underlies the development of a harmful foamy macrophage phenotype in these disorders. To date, the molecular mechanisms that underlie dysregulation of cellular lipid metabolism are not fully understood. Here, we show that the ubiquitin-proteasome system controls turnover of the cholesterol efflux transporter ATP-binding cassette A1 (ABCA1) in lipid-loaded macrophages in the brain. We report that sustained intracellular accumulation of myelin-derived lipids promotes the abundance and activity of ubiquitin-protein E3 ligase A (UBE3A) in macrophages, which in turn stimulates ABCA1 ubiquitination and subsequent degradation. UBE3A-mediated ABCA1 degradation boosted cellular lipid accumulation, and induced the formation of an inflammatory macrophage phenotype that impaired remyelination. By using RNA sequencing analysis, we further established Tat-interacting protein 30 (TIP30), an inhibitor of importin β-mediated nuclear import, as an essential regulator of cytosolic UBE3A levels. Collectively, our findings identify UBE3A as a driver of foam cell formation, and indicate that targeting UBE3A-mediated ABCA1 degradation is a promising strategy to mend faulty lipid metabolism in foamy macrophages and enhance central nervous system repair.