The time course of signaling by peptide hormones, neural peptides, and other neuromodulators depends on their storage inside dense core vesicles (DCVs). Adaptor protein 3 (AP-3) assembles the membrane proteins that confer regulated release of DCVs and is thought to promote their trafficking from endosomes directly to maturing DCVs. We now find that regulated monoamine release from DCVs requires sorting nexin 5 (SNX5). Loss of SNX5 disrupts trafficking of the vesicular monoamine transporter (VMAT) to DCVs. The mechanism involves a role for SNX5 in retrograde transport of VMAT from endosomes to the TGN. However, this role for SNX5 conflicts with the proposed function of AP-3 in trafficking from endosomes directly to DCVs. We now identify a transient role for AP-3 at the TGN, where it associates with DCV cargo. Thus, retrograde transport from endosomes by SNX5 enables DCV assembly at the TGN by AP-3, resolving the apparent antagonism. A novel role for AP-3 at the TGN has implications for other organelles that also depend on this adaptor.

中文翻译：

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SNX5 将单胺转运蛋白靶向 TGN，通过 AP-3 组装成致密核心囊泡

肽激素、神经肽和其他神经调节剂发出信号的时间过程取决于它们在致密核心囊泡 (DCV) 内的存储。衔接蛋白 3 (AP-3) 组装膜蛋白，从而实现 DCV 的调节释放，并被认为可以促进它们从内体直接运输到成熟的 DCV。我们现在发现 DCV 中单胺的调节释放需要分选 nexin 5 (SNX5)。SNX5 的缺失会扰乱囊泡单胺转运蛋白 (VMAT) 向 DCV 的运输。该机制涉及 SNX5 在 VMAT 从内体逆行转运至 TGN 中的作用。然而，SNX5 的这一作用与 AP-3 从内体直接运输到 DCV 的拟议功能相冲突。我们现在确定了 AP-3 在 TGN 中的暂时角色，它与 DCV 货物相关联。因此，SNX5 从内体的逆行转运使得 AP-3 在 TGN 处组装 DCV，从而解决了明显的拮抗作用。AP-3 在 TGN 中的新作用对也依赖于该接头的其他细胞器具有影响。