Retromer

Retromer is a conserved multi-protein complex that mediates cargo sorting and trafficking within the endosomal system, primarily directing endosome-to-Golgi retrieval and, in some cases, recycling cargo back to the plasma membrane. By retrieving certain receptors and enzymes from endosomes, retromer prevents their degradation in lysosomes and supports proper signaling and organelle function.

The core of the retromer complex is a cargo-selective trimer composed of VPS35, VPS29, and VPS26. This trimer associates with a membrane-bound sorting nexin (SNX) subcomplex, typically including SNX1 or SNX2 together with SNX5 or SNX6, which contain BAR domains that help sculpt membrane tubules. The SNX-BAR subcomplex works with the retromer core to form tubular carriers that carry selected cargos away from late endosomes.

Cargo recognition involves interactions between the VPS35–VPS29–VPS26 trimer and sorting motifs on cargo proteins' cytoplasmic tails. Retromer function is coordinated with other factors on endosomes, including the actin-nucleating WASH complex, which promotes tubule formation and scission, and Rab7 GTPase, which helps recruit retromer to late endosomes.

Prominent cargos include the cation-independent mannose-6-phosphate receptor (CI-MPR) and other lysosomal sorting receptors, as well as proteins such as TGN38/46 and sortilin, which are recycled to the Golgi apparatus or, in some contexts, back to the plasma membrane.

Dysfunction or mutation of retromer components has been linked to neurodegenerative diseases, notably Parkinson’s disease and Alzheimer’s disease, highlighting retromer’s role in maintaining neuronal protein trafficking and cellular homeostasis.