Multimeric cargo adaptors such as AP2 play central roles in intracellular membrane trafficking. We recently discovered that the assembly of the AP2 adaptor complex, a key player in clathrin-mediated endocytosis, is a highly organized process controlled by alpha- and gamma-adaptin-binding protein (AAGAB, also known as p34). In this study, we demonstrate that besides AP2, AAGAB also regulates the assembly of AP1, a cargo adaptor involved in clathrin-mediated transport between the trans-Golgi network and the endosome. However, AAGAB is not involved in the formation of other adaptor complexes, including AP3. AAGAB promotes AP1 assembly by binding and stabilizing the γ and σ subunits of AP1, and its mutation abolishes AP1 assembly and disrupts AP1-mediated cargo trafficking. Comparative proteomic analyses indicate that AAGAB mutation massively alters surface protein homeostasis, and its loss-of-function phenotypes reflect the synergistic effects of AP1 and AP2 deficiency. Taken together, these findings establish AAGAB as an assembly chaperone for both AP1 and AP2 adaptors and pave the way for understanding the pathogenesis of AAGAB-linked diseases.

中文翻译：

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AAGAB 是调节 AP1 和 AP2 网格蛋白接头的装配伴侣。

AP2 等多聚体货物适配器在细胞内膜运输中起着核心作用。我们最近发现，AP2 衔接复合物的组装是网格蛋白介导的内吞作用的关键参与者，它是一个高度组织化的过程，由 alpha 和 gamma 适应蛋白结合蛋白（AAGAB，也称为 p34）控制。在这项研究中，我们证明除了 AP2 之外，AAGAB 还调节 AP1 的组装，AP1 是一种货物适配器，参与跨高尔基体网络和核内体之间网格蛋白介导的运输。然而，AAGAB 不参与其他衔接复合物的形成，包括 AP3。AAGAB 通过结合和稳定 AP1 的 γ 和 σ 亚基来促进 AP1 组装，其突变消除了 AP1 组装并破坏了 AP1 介导的货物运输。比较蛋白质组学分析表明，AAGAB 突变极大地改变了表面蛋白稳态，其功能丧失表型反映了 AP1 和 AP2 缺陷的协同效应。综上所述，这些发现将 AAGAB 确立为 AP1 和 AP2 衔接子的装配伴侣，并为理解 AAGAB 相关疾病的发病机制铺平了道路。