Selective degradation of pathological protein aggregates while sparing monomeric forms is of major therapeutic interest. The E3 ligase tripartite motif–containing protein 21 (TRIM21) degrades antibody-bound proteins in an assembly state–specific manner due to the requirement of TRIM21 RING domain clustering for activation, yet effective targeting of intracellular assemblies remains challenging. Here, we fused the RING domain of TRIM21 to a target-specific nanobody to create intracellularly expressed constructs capable of selectively degrading assembled proteins. We evaluated this approach against green fluorescent protein–tagged histone 2B (H2B-GFP) and tau, a protein that undergoes pathological aggregation in Alzheimer’s and other neurodegenerative diseases. RING-nanobody degraders prevented or reversed tau aggregation in culture and in vivo, with minimal impact on monomeric tau. This approach may have therapeutic potential for the many disorders driven by intracellular protein aggregation.

中文翻译：

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通过聚集激活的降解剂选择性去除病理性 tau


在保留单体形式的同时选择性降解病理性蛋白质聚集体具有主要的治疗意义。由于 TRIM21 RING 结构域聚集激活，包含 E3 连接酶三方基序的蛋白 21 （TRIM21） 以组装状态特异性方式降解抗体结合蛋白，但有效靶向细胞内组装仍然具有挑战性。在这里，我们将 TRIM21 的 RING 结构域与靶标特异性纳米抗体融合，以创建能够选择性降解组装蛋白的细胞内表达构建体。我们针对绿色荧光蛋白标记的组蛋白 2B （H2B-GFP） 和 tau 评估了这种方法，tau 是一种在阿尔茨海默病和其他神经退行性疾病中经历病理聚集的蛋白质。RING 纳米抗体降解剂可防止或逆转培养物和体内的 tau 聚集，对单体 tau 的影响最小。这种方法可能对细胞内蛋白质聚集驱动的许多疾病具有治疗潜力。