Navigating the Controversies of Retromer-Mediated Endosomal Protein Sorting.

Yingfeng Tu,Matthew N. J. Seaman

doi:10.3389/fcell.2021.658741

Abstract

The retromer complex was first identified more than 20 years ago through studies conducted in the yeast Saccharomyces cerevisiae. Data obtained using many different model systems have revealed that retromer is a key component of the endosomal protein sorting machinery being necessary for recognition of membrane “cargo” proteins and formation of tubular carriers that function as transport intermediates. Naturally, over the course of time and with literally hundreds of papers published on retromer, there have arisen disparities, conflicting observations and some controversies as to how retromer functions in endosomal protein sorting – the most note-worthy being associated with the two activities that define a vesicle coat: cargo selection and vesicle/tubule formation. In this review, we will attempt to chart a course through some of the more fundamental controversies to arrive at a clearer understanding of retromer.

Highlights

Reviewed by: Roman Polishchuk, Telethon Institute of Genetics and Medicine (TIGEM), Italy Ruben Claudio Aguilar, Purdue University, United States
The retromer complex was first identified more than 20 years ago through studies conducted in the yeast Saccharomyces cerevisiae
Over the course of time and with literally hundreds of papers published on retromer, there have arisen disparities, conflicting observations and some controversies as to how retromer functions in endosomal protein sorting – the most note-worthy being associated with the two activities that define a vesicle coat: cargo selection and vesicle/tubule formation

Summary

DATA SUPPORTING THE INITIAL HYPOTHESES

Subsequent studies in yeast reported that Vps35p could be chemically cross-linked to a membrane protein that undergoes endosome-to-Golgi retrieval. In yeast, the retromer proteins form a stable heteropentameric complex that associates with endosomes via the PtdIns 3P-binding properties of the Vps5-Vps dimer, in mammalian cells, the Vps35-Vps29Vps dimer requires the small GTPase Rab for its recruitment to endosomes (Rojas et al, 2008; Seaman et al, 2009). In addition to Rab, the SNX3 protein is required for recruitment of the Vps35-Vps29-Vps trimer, an interaction that appears conserved in yeast where SNX3 is known as Grd19p and operates with retromer in endosome-to-Golgi retrieval (Strochlic et al, 2007; Harterink et al, 2011; Vardarajan et al, 2012). Detailed high resolution microscopy of mammalian cells subsequently revealed that the Vps35-Vps29-Vps trimer and SNX dimer were detectable on distinct regions of endosomal membranes consistent with there being no stable association between the two complexes (Kvainickas et al, 2017a). The lack of any robust association between the Vps35-Vps29-Vps trimer and the SNX-BAR dimer in mammalian cells led to the term retromer being applied to just the trimer, sometimes with additional descriptors so that “core retromer” or “retromer cargo-selective complex” were used to describe the Vps35-Vps29-Vps trimer

SORTING MOTIFS AND STRUCTURES

ARCHES THAT DRIVE TUBULATION?

CONNECTIONS TO THE CYTOSKELETON

CONTROVERSIES RESOLVED?