Retromer: A Master Conductor of Endosome Sorting

Abstract

The endosomal network comprises an interconnected network of membranous compartments whose primary function is to receive, dissociate, and sort cargo that originates from the plasma membrane and the biosynthetic pathway. A major challenge in cell biology is to achieve a thorough molecular description of how this network operates, and in so doing, how defects contribute to the etiology and pathology of human disease. We discuss the increasing body of evidence that implicates an ancient evolutionary conserved complex, termed "retromer," as a master conductor in the complex orchestration of multiple cargo-sorting events within the endosomal network.

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

“…Endosomal dysfunction, characterized by enlarged endosomes, is likely mediated by endosomal transport and trafficking defects. Retromer has emerged as a master regulator of endosomal transport [42]. And in this way, by targeting the retromer, we are targeting the unified cell biology of AD.…”

Rab Proteins and the Compartmentalization of the Endosomal System

“…A short carboxyterminal signal (VxPx) in the cargo proteins serves to bind Arf4 and recruit a cohort of Rab GTPases (Rab6, Rab8, and Rab11) and regulatory proteins (ASAP1, Rabin8) that act in a concerted cascade to promote the ciliary targeting of their cargo (Mazelova et al 2009;Ward et al 2011Ward et al , 2012. Rab5, Rab7, and Rab9 are implicated in endosomal cargo sorting mediated by retromer-a tripartite complex of Vps26, Vps29, and Vps35-and sorting nexins (Seaman 2012;Vardarajan et al 2012;Dong et al 2013;Pfeffer 2013b;Seaman et al 2013; see also Burd and Cullen 2014). Rab5 activation is only indirectly required, but GTP-bound Rab7 is pivotal in the membrane recruitment of the retromer complex, and TBC1D5, one of two GAPs for Rab7, causes inactivation of the GTPase and retromer release from endosomal membranes.…”

Endocytosis: Past, Present, and Future

“…Several articles are then devoted to the signals and mechanisms governing these sorting decisions. They cover the molecular machineries responsible for the compartmental organization and function of endosomes (WandingerNess and Zerial 2014) and sorting and transport along endolysosomal pathways (Bissig and Gruenberg 2013;Henne et al 2013;Burd and Cullen 2014;Piper et al 2014). Lysosomes and lysosome-related organelles are discussed in the article by Luzio et al 2014).…”