The early endosome: a busy sorting station for proteins at the crossroads

Abstract

Endocytosis marks the entry of internalized receptors into the complex network of endocytic trafficking pathways. Endocytic vesicles are rapidly targeted to a distinct membrane-bound endocytic organelle referred to as the early endosome. Despite the existence of numerous internalization routes, early endosomes (EE) serve as a focal point of the endocytic pathway. Sorting events initiated at this compartment determine the subsequent fate of internalized proteins and lipids, destining them either for recycling to the plasma membrane, degradation in lysosomes or delivery to the trans-Golgi network. Sorting of endocytic cargo to the latter compartments is accomplished through the formation of distinct microdomains within early endosomes, through the coordinate recruitment and assembly of the sorting machinery. An elaborate network of interactions between endocytic regulatory proteins ensures synchronized sorting of cargo to microdomains followed by morphological changes at the early endosomal membranes. Consequently, the cargo targeted either for recycling back to the plasma membrane, or for retrograde transport to the trans-Golgi network, localizes to newly-formed tubular membranes. With a high ratio of membrane surface to lumenal volume, these tubules effectively concentrate the recycling cargo, ensuring efficient transport out of the EE. Conversely, receptors sorted for degradation cluster at the flat clathrin lattices involved in invaginations of the limiting membrane, associating with newly formed intralumenal vesicles. In this review we will discuss the characteristics of early endosomes, their role in the regulation of endocytic transport, and their aberrant function in a variety of diseases.

Fig. 1

HeLa cells on coverslips were either mock-treated or treated with specific siRNA oligonucleotides against EHD3 (Naslavsky et al., 2006; Sharma et al., 2008), EHD4 (Sharma et al., 2008), Rabenosyn-5 and EHD1 (Naslavsky et al., 2004) as described previously. After treatment with siRNA, cells were fixed and stained for endogenous EEA1 followed by the goat anti-mouse Alexa-488 secondary antibodies. Depletion of EHD3, EHD4 and Rabenosyn-5 induced formation of enlarged early endosomes while depletion of EHD1 caused accumulation of EEA1 in the ERC.

Fig. 2

Endocytic sorting at the EE. Delivery of internalized cargo molecules to EE is mediated by GTP-Rab5 and its effector EEA1 in a series of homotypic fusion events. Cargo can then either be sorted for recycling back to the plasma membrane in a fast (Rab4-mediated) or slow (Rab4, Rabenosyn-5, EHD3 and/or EHD4-mediated) pathway. Alternatively, in the case of mono-ubiquitinated cargo, proteins are sorted for lysosomal degradation (via Hrs, Tsg101, ESCRT complex, Rab7) or to the Golgi (via SNX1/2 and EHD1/3).