PDF(Pubmed)
Abstract：
Selective retrograde transport from endosomes back to the trans-Golgi network (TGN) is important for maintaining protein homeostasis, recycling receptors, and returning molecules that were transported to the wrong compartments. Two important transmembrane proteins directed to this pathway are the Cation-Independent Mannose-6-phosphate receptor (CI-MPR) and the ATP7B copper transporter. Among CI-MPR functions is the delivery of acid hydrolases to lysosomes, while ATP7B facilitates the transport of cytosolic copper ions into organelles or the extracellular space. Precise subcellular localization of CI-MPR and ATP7B is essential for the proper functioning of these proteins. This study shows that both CI-MPR and ATP7B interact with a variant of the clathrin adaptor 1 (AP-1) complex that contains a specific isoform of the γ-adaptin subunit called γ2. Through synchronized anterograde trafficking and cell-surface uptake assays, we demonstrated that AP-1γ2 is dispensable for ATP7B and CI-MPR exit from the TGN while being critically required for ATP7B and CI-MPR retrieval from endosomes to the TGN. Moreover, AP-1γ2 depletion leads to the retention of endocytosed CI-MPR in endosomes enriched in retromer complex subunits. These data underscore the importance of AP-1γ2 as a key component in the sorting and trafficking machinery of CI-MPR and ATP7B, highlighting its essential role in the transport of proteins from endosomes.
摘要：
从内体到跨高尔基网络（TGN）的选择性逆行转运对于维持蛋白质稳态很重要，回收受体，并返回被运送到错误隔室的分子。针对该途径的两种重要的跨膜蛋白是阳离子非依赖性甘露糖-6-磷酸受体(CI-MPR)和ATP7B铜转运蛋白。AmongCI-MPR功能是将酸性水解酶递送到溶酶体，而ATP7B有助于将胞质铜离子转运到细胞器或细胞外空间。CI-MPR和ATP7B的精确亚细胞定位对于这些蛋白质的正常功能至关重要。这项研究表明，CI-MPR和ATP7B都与网格蛋白衔接子1（AP-1）复合物的变体相互作用，该变体包含称为γ2的γ-适应蛋白亚基的特定同工型。通过同步的顺行运输和细胞表面摄取测定，我们证明了AP-1γ2对于ATP7B和CI-MPR退出TGN是可有可无的，同时对于从内体到TGN的ATP7B和CI-MPR检索至关重要。此外，AP-1γ2耗竭导致在富含逆转录复合物亚基的内体中保留内吞细胞的CI-MPR。这些数据强调了AP-1γ2作为CI-MPR和ATP7B的分类和贩运机制中的关键组成部分的重要性，强调它在内体蛋白质转运中的重要作用。
