中文摘要：

泡沫巨噬细胞的积累是脱髓鞘脑疾病的病理特征。代谢紊乱和细胞内脂质的外排是这些疾病中有害的泡沫巨噬细胞表型发展的根本原因，但其背后的分子机制尚不明确。在这里，我们展示了泛素-蛋白酶体系统控制大脑中脂质负荷巨噬细胞的胆固醇外排转运蛋白ATP结合盒A1（ABCA1）的周转。我们报告说，髓鞘衍生脂质的积累促进了巨噬细胞中泛素-蛋白E3连接酶A（UBE3A）的丰度和活性，这刺激了ABCA1的泛素化及随后的降解。这增加了细胞脂质的积累并诱导了损害再髓鞘化的炎性巨噬细胞表型。我们进一步确定参与Tat的蛋白30（TIP30），作为介导进口蛋白β的核内导入的抑制剂，是细胞质UBE3A水平的一个重要调节因子。总之，我们的发现将UBE3A确定为泡沫细胞形成的驱动因素，并表明靶向UBE3A介导的ABCA1降解是增强中枢神经系统修复的一个有前景的策略。

英文摘要：

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.

论文信息：

论文题目：UBE3A promotes foam cell formation and counters remyelination by targeting ABCA1 for proteasomal degradation

期刊名称：Nature Communications

时间期卷：16, Article number: 8077 (2025)

在线时间：2025年8月29日

DOI：doi.org/10.1038/s41467-025-62053-w

产品信息：

货号：CP-005-005

规格：5ml+5ml

品牌：Liposoma

产地：荷兰

名称：Clodronate Liposomes and Control Liposomes

办事处：Target Technology(靶点科技)

Clodronate Liposomes氯膦酸盐脂质体清除泡沫巨噬细胞，泡沫巨噬细胞含有过量的细胞内来源于髓鞘的脂质，导致多发性硬化症（MS）等神经退行性疾病的病理。虽然对富含脂质的结构，如改良的脂蛋白和髓鞘的摄取，将巨噬细胞表型重塑为通常与组织修复和免疫抑制相关的表型，但这种解决疾病的表型仅是短暂的。我们和其他研究者发现，巨噬细胞中髓鞘来源脂质的过度积累，尤其在衰老过程中，使泡沫细胞倾向于更具炎症性和促进疾病的表型。这种有害表型的诱导与大脑修复模型中损伤恢复受损密切相关。从机制上讲，细胞内脂质的新陈代谢失调，主要由于胆固醇外流减少，导致细胞脂质含量失衡和有害泡沫巨噬细胞亚群的发展。荷兰Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于Nature Communications：氯膦酸盐脂质体clodronateliposomes体外清除脑切片Cerebellar brain slices 巨噬细胞。

Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体体外清除脑切片巨噬细胞的材料和方法：

Brain slice cultures

Cerebellar slices were obtained from male and female wild-type and Ube3a?/? P9-P11 mouse pups as described previously8,66. Briefly, cerebellar parasagittal slices (300-µm thick) were cut on a MacIlwain tissue chopper and transferred onto membranes of 30-mm Millipore culture inserts with a 0.4-μm pore size (Millicell; Millipore). Slices were maintained in culture on top of the membranes in six-well plates containing 1?ml of medium [MEM (Thermo Fisher Scientific, 32360-026) supplemented with 25% horse serum (Life Technologies, S-HS-EU-015), 25% Hanks’ balanced salt solution (Invitrogen, 14025092), 1% P/S, 1% Glutamax (Sigma, 35050-038), 1.3% glucose (Sigma, G8644), and 1.1% 1?M HEPES (Thermo Fisher Scientific, 15630-080) at 37?°C, 5% CO2. For phagocyte depletion, slices were treated with clodronate or empty liposomes (0.5?mg/ml, LIPOSOMA) immediately after isolation for 24?h. Slices were repleted with 4?×?103 LPS- (100?ng/µl, Sigma, 437627, 18?h) or IL4-stimulated (20?ng/µL, Peprotech, 214-14, 18?h) wild-type or Ube3a?/? BMDMs by adding them directly to the slice in a 1.5?µl drop, without touching the slice. Slices were left to recover for 2 days, after which demyelination was induced by treating the slices with lysolecithin (0.5?mg/ml, Sigma, 62963) for 16?h. Afterward, slices were washed and kept in culture for 6 days, followed by histological and biochemical analysis.

脑切片体外巨噬细胞清除材料和方法文献截图：