VPS35

VPS35, or vacuolar protein sorting-associated protein 35, is a conserved component of the retromer complex that mediates endosome-to-Golgi retrieval of transmembrane receptors and other cargo. It functions as part of a core cargo-recognition module composed with VPS29 and VPS26, with two isoforms of VPS26 (VPS26A and VPS26B) providing cargo specificity. The retromer complex associates with sorting nexin proteins to form coat structures on endosomal membranes that drive the formation of tubular carriers.

In its primary role, VPS35 helps select and sort cargo for trafficking away from endosomes toward the trans-Golgi network or, in some cases, back to the plasma membrane. This process is essential for the proper recycling and localization of a range of receptors and hydrolases, including the cation-independent mannose-6-phosphate receptor and other cargoes such as SorL1. The retromer complex operates in conjunction with different SNX (sorting nexin) subcomplexes, forming variants that accommodate diverse trafficking routes.

Genetically, VPS35 encodes the VPS35 protein in humans. Pathogenic variants have been linked to neurodegenerative disease; the most well-known is the D620N missense mutation, which has been associated with autosomal dominant Parkinson’s disease. This and related studies highlight the importance of retromer function for neuronal health, and research continues into therapies aimed at stabilizing or enhancing retromer activity as a potential neuroprotective strategy.

VPS35 is broadly conserved across eukaryotes and is a key component of intracellular sorting and trafficking pathways. Its proper function supports cellular homeostasis by maintaining correct receptor localization and cargo recycling within the endosomal system.