Synthetic autophagy receptor.
Synthetic autophagy receptor.
复制标题
合成自噬受体。
DOI：
10.1080/15548627.2023.2278954
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发表时间：
2024
期刊：
影响因子：
13.3
通讯作者：
Arkin,MichelleR
中科院分区：
文献类型：
--
作者：
Jiang,Ziwen;Kuo,Yu-Hsuan;Arkin,MichelleR
巨型自噬/自噬受体将它们的底物定位于吞噬载体，以便随后在自噬体内进行隔离。在哺乳动物细胞吞噬体膜的扩张过程中，自噬受体同时与泛素化底物和扩张膜上的Lc3/GABARAP蛋白相互作用。在这篇文章中，我们总结和讨论了我们在合成自噬受体(AceTAC)方面的最新研究进展。这一系列AceTAC是通过设计哺乳动物主要的自噬受体SQSTM1/p62(隔离小体1)的基本相互作用结构域和基序来设计的。特别是，我们用目标特异性抗体取代了SQSTM1的泛素相关结构域，重定向了野生型SQSTM1的双功能相互作用，并将降解目标定向到自噬过程中。我们成功地使用AceTAC降解器对易于聚集的蛋白质进行了靶向降解。此外，我们提出了一个模型系统，该系统具有通过自噬机制诱导细胞器定向降解的指南。
Macroautophagy/autophagy receptors target their substrates to phagophores for subsequent sequestration within autophagosomes. During phagophore membrane expansion in mammalian cells, autophagy receptors simultaneously interact with the ubiquitinated substrates and the LC3/GABARAP proteins on the expanding membrane. In this punctum, we summarize and discuss our recent research progress on synthetic autophagy receptors (AceTACs). The series of AceTACs were designed by engineering the essential interacting domains and motifs of SQSTM1/p62 (sequestosome 1), a major mammalian autophagy receptor. Particularly, we replaced the ubiquitin-associated domain of SQSTM1 with a target-specific antibody, redirecting the bifunctional interactions of wild-type SQSTM1 and directing the degradation target into the autophagy process. We successfully demonstrated the targeted degradation of aggregation-prone proteins using the AceTAC degraders. Moreover, we presented a model system with a guideline to induce targeted degradation of organelles through the autophagy machinery.