EHDs meet the retromer: Complex regulation of retrograde transport

Abstract

Retrograde trafficking mediates the transport of endocytic membranes from endosomes to the trans-Golgi network (TGN). Dysregulation of these pathways can result in multiple ailments, including late-onset Alzheimer disease. One of the key retrograde transport regulators, the retromer complex, is tightly controlled by many factors, including the C-terminal Eps15 homology domain (EHD) proteins. This mini-review focuses on recent findings and discusses the regulation of the retromer complex by EHD proteins and the novel EHD1 interaction partner, Rabankyrin-5 (Rank-5).

Figure 1. Retrograde transport and EHD proteins. Retrograde transport of endocytic membranes occurs from early endosomes, late endosomes and/or recycling endosomes to the TGN. EHD1 and EHD3 interact with the retromer complex and regulate retromer-mediated membrane transport. For simplicity, only EHD proteins and their interaction partners are shown.

Figure 2. Schematic diagram of Rank-5 domain architecture. Rank-5 contains a C-terminal BTB domain and an N-terminal FYVE domain, with 21 consecutive ankyrin repeats in between. The NPFED motif localizes to the fifth ankyrin repeat.

Figure 3. Proposed model for Rank-5 function. Rank-5 is required for the formation of macropinosomes and plays a role in homotypic early-endosome fusion. Through binding to EHD1 and MICAL-L1, Rank-5 is recruited to the retromer and influences retromer-mediated retrograde transport. Furthermore, depletion of either Rank-5 or EHD1 affects VSV-G secretion, possibly through its effect on the homeostasis of the TGN. EE, early endosomes.