The Role of the Clathrin Adaptor AP-1: Polarized Sorting and Beyond

Abstract

The selective transport of proteins or lipids by vesicular transport is a fundamental process supporting cellular physiology. The budding process involves cargo sorting and vesicle formation at the donor membrane and constitutes an important process in vesicular transport. This process is particularly important for the polarized sorting in epithelial cells, in which the cargo molecules need to be selectively sorted and transported to two distinct destinations, the apical or basolateral plasma membrane. Adaptor protein (AP)-1, a member of the AP complex family, which includes the ubiquitously expressed AP-1A and the epithelium-specific AP-1B, regulates polarized sorting at the trans-Golgi network and/or at the recycling endosomes. A growing body of evidence, especially from studies using model organisms and animals, demonstrates that the AP-1-mediated polarized sorting supports the development and physiology of multi-cellular units as functional organs and tissues (e.g., cell fate determination, inflammation and gut immune homeostasis). Furthermore, a possible involvement of AP-1B in the pathogenesis of human diseases, such as Crohn's disease and cancer, is now becoming evident. These data highlight the significant contribution of AP-1 complexes to the physiology of multicellular organisms, as master regulators of polarized sorting in epithelial cells.

Figure 1

The AP complexes. Schematic representation of the AP complex family. Seven AP complexes have been identified to date. They share the overall composition of the constituting subunits: two large subunits, one medium subunit and one small subunit. The five complexes depicted at the top (AP-1A, AP-2, AP-3A, AP-4 and AP-5) are widely expressed, whereas the two complexes shown at the bottom (AP-1B and AP-3B) are expressed in a tissue-specific manner. They localize to distinct, yet partially overlapping, organelles. The organelle membrane at which each complex is localized (for controlling protein sorting) is shown below the complex. TGN, trans-Golgi network.

Figure 2

The post-Golgi network controlled by the AP complexes. The AP complexes are widely distributed throughout the post-Golgi network. AP-1A is localized at the TGN and endosomes and regulates the TGN-endosomal and the TGN-basolateral plasma membrane pathways. AP-2 is recruited to the plasma membrane for regulating endocytosis. AP-3A regulates the endosomal and the lysosomal trafficking pathways. AP-3B is involved in the biogenesis of specialized organelles, such as synaptic vesicles and dense core vesicles. AP-4 is involved in the TGN-endosomal and the TGN-basolateral plasma membrane pathways. A recently-identified AP-5 has been shown to localize at the endo-lysosomes. The epithelium-specific AP-1B and the ubiquitously-expressed AP-1A localize at the TGN and/orat the recycling endosome and control the polarized sorting to the basolateral plasma membrane. Defects in the localization of the apical proteins have been reported in a loss-of-function mutant of AP-1B, suggesting that AP-1B could be indirectly involved in the apical protein sorting. See the text for details.