Targeted protein degradation (TPD) utilizes molecular glues or proteolysis-targeting chimeras (PROTACs) to eliminate disease-causing proteins by promoting their interaction with E3 ubiquitin ligases. Current TPD approaches are limited by reliance on a small number of constitutively active E3 ubiquitin ligases. Here, we report that (S)-ACE-OH, a metabolite of the antipsychotic drug acepromazine, acts as a molecular glue to induce an interaction between the E3 ubiquitin ligase TRIM21 and the nucleoporin NUP98, leading to the degradation of nuclear pore proteins and disruption of nucleocytoplasmic trafficking. Functionalization of acepromazine into PROTACs enabled selective degradation of multimeric proteins, such as those within biomolecular condensates, while sparing monomeric proteins. This selectivity is consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies cause diseases such as autoimmunity, neurodegeneration, and cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.

中文翻译：

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通过基于 TRIM21 的分子胶和 PROTAC 降解剂对多聚体蛋白进行选择性降解


靶向蛋白降解 （TPD） 利用分子胶或蛋白水解靶向嵌合体 （PROTAC），通过促进致病蛋白与 E3 泛素连接酶的相互作用来消除致病蛋白。目前的 TPD 方法受到对少量组成型活性 E3 泛素连接酶的依赖的限制。在这里，我们报道了 （S）-ACE-OH 是抗精神病药物乙酰丙嗪的代谢产物，作为分子胶诱导 E3 泛素连接酶 TRIM21 和核孔蛋白 NUP98 之间的相互作用，导致核孔蛋白降解和核质运输中断。乙酰丙嗪功能化为 PROTAC 能够选择性降解多聚体蛋白，例如生物分子凝聚物中的蛋白，同时保留单体蛋白。这种选择性与 TRIM21 激活的底物诱导聚集的要求一致。由于异常的蛋白质组装会导致自身免疫、神经退行性和癌症等疾病，我们的研究结果强调了基于 TRIM21 的多聚体选择性降解剂作为解决这些疾病直接原因的策略的潜力。