Receptor Recycling by Retromer

Abstract

The highly conserved retromer complex controls the fate of hundreds of receptors that pass through the endolysosomal system and is a central regulatory node for diverse metabolic programs. More than 20 years ago, retromer was discovered as an essential regulator of endosome-to-Golgi transport in yeast; since then, significant progress has been made to characterize how metazoan retromer components assemble to enable its engagement with endosomal membranes, where it sorts cargo receptors from endosomes to the trans-Golgi network or plasma membrane through recognition of sorting motifs in their cytoplasmic tails. In this review, we examine retromer regulation by exploring its assembled structure with an emphasis on how a range of adaptor proteins shape the process of receptor trafficking. Specifically, we focus on how retromer is recruited to endosomes, selects cargoes, and generates tubulovesicular carriers that deliver cargoes to target membranes. We also examine how cells adapt to distinct metabolic states by coordinating retromer expression and function. We contrast similarities and differences between retromer and its related complexes: retriever and commander/CCC, as well as their interplay in receptor trafficking. We elucidate how loss of retromer regulation is central to the pathology of various neurogenerative and metabolic diseases, as well as microbial infections, and highlight both opportunities and cautions for therapeutics that target retromer. Finally, with a focus on understanding the mechanisms that govern retromer regulation, we outline new directions for the field moving forward.

Keywords:

• retromer
• VPS35
• endosome
• neurodegeneration
• cell trafficking

ACKNOWLEDGMENTS

We thank all lab members for insightful discussions and advice. Illustrations were generated under license with Adobe Illustrator and Biorender.

AUTHORS’ CONTRIBUTIONS

J.M.C. conceived the review, wrote and edited the text, and generated the figures. T.J.S., D.D. and S.K. edited the manuscript and supervised the project.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Additional information

Funding

This investigation was supported by Lysosomal Health in Ageing at SAHMRI. J.M.C. was supported by a Research Training Stipend. and a Commonwealth Scholarship from the Australian Government, and a Research Degree Excellence Grant from UniSA. D.D. was supported by a National Health and Medical Research Council (NHMRC) Project Grant [1124490], an Australian Research Council Discovery Project [DP10100665] and a UniSA Support Package to S.K. S.K. was supported by a NHMRC Senior Principal Research Fellowship [GNT1103006] and a L3 Investigator Grant [2007739].