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Degradation of lipid droplets by chimeric autophagy-tethering compounds
Cell Research ( IF 28.1 ) Pub Date : 2021-07-08 , DOI: 10.1038/s41422-021-00532-7
Yuhua Fu 1 , Ningxie Chen 1 , Ziying Wang 1 , Shouqing Luo 2 , Yu Ding 1 , Boxun Lu 1
Affiliation  

Degrading pathogenic proteins by degrader technologies such as PROTACs (proteolysis-targeting chimeras) provides promising therapeutic strategies, but selective degradation of non-protein pathogenic biomolecules has been challenging. Here, we demonstrate a novel strategy to degrade non-protein biomolecules by autophagy-tethering compounds (ATTECs), using lipid droplets (LDs) as an exemplar target. LDs are ubiquitous cellular structures storing lipids and could be degraded by autophagy. We hypothesized that compounds interacting with both the LDs and the key autophagosome protein LC3 may enhance autophagic degradation of LDs. We designed and synthesized such compounds by connecting LC3-binding molecules to LD-binding probes via a linker. These compounds were capable of clearing LDs almost completely and rescued LD-related phenotypes in cells and in two independent mouse models with hepatic lipidosis. We further confirmed that the mechanism of action of these compounds was mediated through LC3 and autophagic degradation. Our proof-of-concept study demonstrates the capability of degrading LDs by ATTECs. Conceptually, this strategy could be applied to other protein and non-protein targets.



中文翻译:

嵌合自噬束缚化合物降解脂滴

通过 PROTAC(蛋白水解靶向嵌合体)等降解技术降解致病蛋白提供了有前途的治疗策略,但非蛋白质致病生物分子的选择性降解一直具有挑战性。在这里,我们展示了一种通过自噬束缚化合物 (ATTEC) 降解非蛋白质生物分子的新策略,使用脂滴 (LD) 作为示例目标。LDs 是无处不在的细胞结构,储存脂质,可被自噬降解。我们假设与 LD 和关键自噬体蛋白 LC3 相互作用的化合物可能会增强 LD 的自噬降解。我们通过连接子将 LC3 结合分子连接到 LD 结合探针来设计和合成此类化合物。这些化合物能够几乎完全清除 LD,并在细胞和两个独立的肝脂质沉积小鼠模型中挽救 LD 相关表型。我们进一步证实,这些化合物的作用机制是通过 LC3 和自噬降解介导的。我们的概念验证研究证明了 ATTEC 降解 LD 的能力。从概念上讲,该策略可以应用于其他蛋白质和非蛋白质目标。

更新日期:2021-07-08
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