Trafficking of proteins from endosomes to the trans-Golgi network is essential for protein sorting, recycling and transport to the appropriate locations in the cell. The retromer complex mediates this process for many transmembrane proteins. Retromer is known to interact with γ-secretase, an enzyme commonly mutated in Alzheimer’s disease that cleaves transmembrane proteins. However, the function of this interaction and role of γ-secretase in protein trafficking is currently unclear. In this study (Takeo et al., 2025), Daniel DiMaio and colleagues perform co-immunoprecipitation and proximity ligation assays to show that γ-secretase interacts with proteins transported by retromer, even in the absence of retromer. They also confirm that γ-secretase and retromer interact, but find that this interaction is reduced by inhibition of γ-secretase activity. Loss of γ-secretase activity leads to endosomal accumulation of multiple retromer target proteins, indicating impaired trafficking. However, loss of either retromer or γ-secretase does not affect the other’s localization, expression levels or ability to interact with the transport cargo. Based on these results, the authors propose a new role for γ-secretase in promoting efficient protein trafficking by retromer. Improved understanding of this previously unknown function of γ-secretase has implications in Alzheimer’s and Parkinson’s diseases, where mutant γ-secretase could cause pathogenic effects by impacting protein transport.
