The two clathrin isoforms, CHC17 and CHC22, mediate separate intracellular transport routes. CHC17 performs endocytosis and housekeeping membrane traffic in all cells. CHC22, expressed most highly in skeletal muscle, shuttles the glucose transporter GLUT4 from the ERGIC (endoplasmic-reticulum-to-Golgi intermediate compartment) directly to an intracellular GLUT4 storage compartment (GSC), from where GLUT4 can be mobilized to the plasma membrane by insulin. Here, molecular determinants distinguishing CHC22 from CHC17 trafficking are defined. We show that the C-terminal trimerization domain of CHC22 interacts with SNX5, which also binds the ERGIC tether p115. SNX5, and the functionally redundant SNX6, are required for CHC22 localization independently of their participation in the endosomal ESCPE-1 complex. In tandem, an isoform-specific patch in the CHC22 N-terminal domain separately mediates binding to p115. This dual mode of clathrin recruitment, involving interactions at both N- and C-termini of the heavy chain, is required for CHC22 targeting to ERGIC membranes to mediate the Golgi-bypass route for GLUT4 trafficking. Interference with either interaction inhibits GLUT4 targeting to the GSC, defining a bipartite mechanism regulating a key pathway in human glucose metabolism.

中文翻译：

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CHC22 网格蛋白募集到早期分泌途径需要与 SNX5 和 p115 进行双位点相互作用。


两种网格蛋白亚型 CHC17 和 CHC22 介导单独的细胞内转运途径。CHC17 在所有细胞中执行内吞作用和管家膜运输。CHC22 在骨骼肌中表达最为严重，将葡萄糖转运蛋白 GLUT4 从 ERGIC（内质网到高尔基体中间隔室）直接运送到细胞内 GLUT4 储存室 （GSC），从那里 GLUT4 可以通过胰岛素动员到质膜。这里定义了区分 CHC22 和 CHC17 运输的分子决定因素。我们表明 CHC22 的 C 末端三聚体化结构域与 SNX5 相互作用，SNX5 也结合 ERGIC 系绳 p115。SNX5 和功能冗余的 SNX6 是 CHC22 定位所必需的，与它们参与内体 ESCPE-1 复合体无关。同时，CHC22 N 末端结构域中的亚型特异性贴片单独介导与 p115 的结合。这种网格蛋白募集的双重模式，涉及重链 N 端和 C 端的相互作用，是 CHC22 靶向 ERGIC 膜介导 GLUT4 运输的高尔基体旁路途径所必需的。干扰任何一种相互作用都会抑制 GLUT4 靶向 GSC，从而定义调节人类葡萄糖代谢关键途径的二分机制。