Aagab, also known as alpha-and gamma-adaptin-binding protein (p34), is an assembly chaperone that plays a crucial role in intracellular membrane trafficking. It is involved in regulating the assembly of AP1 and AP2 clathrin adaptors, which are key players in clathrin-mediated transport between the trans-Golgi network and the endosome, as well as clathrin-mediated endocytosis [1,2]. This function is essential for processes like nutrient uptake, signal transduction, and synaptic vesicle recycling [3]. Genetic models such as zebrafish mutants and cell-based models with gene knockdown have been valuable for studying Aagab.

In zebrafish, aagab loss-of-function mutants show impaired swimming and early larval mortality. The mutants display subdued calcium responses and local field potential in optic tectal neurons, along with reduced neurotransmitter release, indicating a role in regulating neural activity [3]. In human cells, AAGAB mutations are associated with punctate palmoplantar keratoderma type 1 (PPKP1), a skin disease. These mutations abolish the function of AAGAB in regulating AP2 adaptor assembly [2,5,6,7]. Additionally, AAGAB promotes AP1 assembly by binding and stabilizing its γ and σ subunits, and its mutation disrupts AP1-mediated cargo trafficking [1]. In AAGAB-knockout cells, there is a reduction in AP-4 subunits and accumulation of ATG9A at the trans-Golgi network, suggesting AAGAB also aids in AP-4 complex assembly [4].

In conclusion, Aagab is a vital assembly chaperone for multiple adaptor complexes, significantly influencing intracellular membrane trafficking. Its function has been illuminated through various model-based research, including zebrafish and cell-based knockout studies. Understanding Aagab's role provides insights into diseases such as PPKP1 and potentially other disorders related to defective membrane trafficking and neural function.