The Retromer Complex: From Genesis to Revelations

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 46; no. 7; pp. 608 - 620
• Main Author: Seaman, Matthew N.J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-07-2021
• Subjects: endosome; membrane; neurodegenerative disease; retromer; sorting nexin; therapeutic target; tubules; endosome; membrane; tubules; neurodegenerative disease; retromer; sorting nexin; therapeutic target
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2020.12.009

The retromer complex has a well-established role in endosomal protein sorting, being necessary for maintaining the dynamic localisation of hundreds of membrane proteins that traverse the endocytic system. Retromer function and dysfunction is linked with neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, and many pathogens, both viral and bacterial, exploit or interfere in retromer function for their own ends. In this review, the history of retromer is distilled into a concentrated form that spans the identification of retromer to recent discoveries that have shed new light on how retromer functions in endosomal protein sorting and why retromer is increasingly being viewed as a potential therapeutic target in neurodegenerative disease.
The retromer complex was first identified 22 years ago and is now known to be critical for endosomal protein sorting.Although conserved in evolution, there are important differences in the composition of retromer between simple and higher eukaryotes that impact on its respective roles in different organisms.New insights into how retromer is arranged on the membrane have prompted a re-assessment of how it functions in endosomal protein sorting.Recent biochemical and structural studies have revealed new mechanisms that govern how retromer and associated proteins sort membrane proteins at endosomes.Expanding studies of retromer have revealed that its function is often hijacked or subverted by pathogens – both bacterial or viral - and that retromer dysfunction is linked to several neurodegenerative diseases.Intriguingly, retromer is now being viewed as a potential therapeutic target in diseases such as Alzheimer’s disease where accumulated evidence shows it plays a key role.