Autophagy is responsible for the degradation of large intracellular contents, such as unwanted protein aggregates and organelles. Impaired autophagy can therefore lead to the accumulation of pathological aggregates, correlating with aging and neurodegenerative diseases. However, a broadly applicable methodology is not available for the targeted degradation of protein aggregates or organelles in mammalian cells. Herein, we developed a series of autophagy receptor-inspired targeting chimeras (AceTACs) that can induce the targeted degradation of aggregation-prone proteins and protein aggregates (e.g., huntingtin, TDP-43, and FUS mutants), as well as organelles (e.g., mitochondria, peroxisomes, and endoplasmic reticulum). These antibody-fusion-based AceTAC degraders were designed to mimic the function of autophagy receptors, simultaneously binding with the cellular targets and the LC3 proteins on the autophagosomal membrane, eventually transporting the target to the autophagy-lysosomal process for degradation. The AceTAC degradation system provides design principles for antibody-based degradation through autophagy, largely expanding the scope of intracellular targeted degradation technologies.

中文翻译：

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自噬受体启发的抗体融合蛋白用于靶向细胞内降解


自噬负责大量细胞内内容物的降解，例如不需要的蛋白质聚集体和细胞器。因此，自噬受损会导致病理聚集物的积累，与衰老和神经退行性疾病相关。然而，目前还没有一种广泛适用的方法可用于哺乳动物细胞中蛋白质聚集体或细胞器的靶向降解。在此，我们开发了一系列受自噬受体启发的靶向嵌合体（AceTAC），它们可以诱导易于聚集的蛋白质和蛋白质聚集体（例如亨廷顿蛋白、TDP-43和FUS突变体）以及细胞器（例如、线粒体、过氧化物酶体和内质网）。这些基于抗体融合的 AceTAC 降解剂旨在模拟自噬受体的功能，同时与细胞靶标和自噬体膜上的 LC3 蛋白结合，最终将靶标转运至自噬-溶酶体过程进行降解。 AceTAC降解系统为通过自噬进行抗体降解提供了设计原理，极大地扩展了细胞内靶向降解技术的范围。