Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

Abstract

Cells need to exchange material and information with their environment. This is largely achieved via cell-surface receptors which mediate processes ranging from nutrient uptake to signaling responses. Consequently, their surface levels have to be dynamically controlled. Endocytosis constitutes a powerful mechanism to regulate the surface proteome and to recycle vesicular transmembrane proteins that strand at the plasma membrane after exocytosis. For efficient internalization, the cargo proteins need to be linked to the endocytic machinery via adaptor proteins such as the heterotetrameric endocytic adaptor complex AP-2 and a variety of mostly monomeric endocytic adaptors. In line with the importance of endocytosis for nutrient uptake, cell signaling and neurotransmission, animal models and human mutations have revealed that defects in these adaptors are associated with several diseases ranging from metabolic disorders to encephalopathies. This review will discuss the physiological functions of the so far known adaptor proteins and will provide a comprehensive overview of their links to human diseases.

Keywords: clathrin; endocytosis; internalization; knockout; mouse; neurotransmission; uptake.

Figure 1

The process of endocytosis. (A) Physiological importance of endocytosis for various cellular pathways. Pathological consequences of endocytic defects affecting the different processes are depicted in red. (B) Simplified scheme of Clathrin-mediated endocytosis (B).

Figure 2

Domain structure of the known and proposed endocytic adaptors. Sketch of the domain structure of endocytic adaptor proteins including putative endocytic binding motifs. Domain structures were based on the following references: AP-2 [8], Stonin1/2 [25], FCHO1/2 and SGIP1 [26], AP180 and CALM [27], HIP1 and HIP1R [28], Epsin1/2/3 [29], Eps15 and Eps15R [30], ARH [31], Dab2 [32], Numb and Numbl [33], β-Arrestin1/2 [34], Hrb [35], TTP [36], MACC1 [37].

Figure 3

Endocytic adaptors, KO mouse phenotypes and human diseases. (A) Illustration of phenotypes due to deletion of endocytic adaptors in mice. (B) Illustration of human diseases associated with endocytic adaptors. Diseases caused by specific mutations in endocytic adaptors are highlighted in blue.