PDF(Pubmed)
Abstract：
Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several types of degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux remains unavailable. In this study, we developed a general chemical tool by which given intracellular proteins are targeted to macroautophagy for lysosomal degradation. This platform technology, termed AUTOTAC (AUTOphagy-TArgeting Chimera), employs bifunctional molecules composed of target-binding ligands (TBLs) linked to autophagy-targeting ligands (ATLs). Upon binding to targets via the TBL, the ATL binds the ZZ domain of the otherwise dormant autophagy receptor SQSTM1/p62 (sequestosome 1), which activates SQSTM1 associated with targets and sequesters them into oligomeric species for autophagic targeting and lysosomal degradation. AUTOTACs were used to degrade various oncoproteins or aggregation-prone proteins in neurodegeneration both in vitro and/or in vivo. We suggest that AUTOTAC provides a platform for selective proteolysis as a research tool and in drug development.
摘要：
靶向蛋白质降解允许靶向不可药物的蛋白质用于治疗应用以及消除感兴趣的蛋白质用于研究目的。虽然已经开发了几种类型的利用蛋白酶体或溶酶体的降解剂，同时降解靶标和加速细胞自噬通量的技术仍然不可用。在这项研究中,我们开发了一种通用化学工具，通过该工具，将细胞内蛋白质靶向巨自噬以进行溶酶体降解。这个平台技术，被称为AUTOTAC（自动吞吐嵌合），使用由与自噬靶向配体（ATL）连接的靶结合配体（TBL）组成的双功能分子。通过TBL与靶标结合后，ATL结合其他休眠自噬受体SQSTM1/p62（螯合体1）的ZZ结构域，它激活与靶标相关的SQSTM1，并将它们隔离到寡聚物中以进行自噬靶向和溶酶体降解。AUTOTAC用于在体外和/或体内降解神经变性中的各种癌蛋白或聚集倾向蛋白。我们建议AUTOTAC作为研究工具和药物开发提供了选择性蛋白水解的平台。
