Sorting nexin-21 is a scaffold for the endosomal recruitment of huntingtin

The endo-lysosomal network serves an essential role in determining the fate of endocytosed transmembrane proteins and their associated proteins and lipids. Sorting nexins (SNXs) play a central role in the functional organisation of this network. Comprising over 30 proteins in humans, SNXs are classified into sub-groups based on the presence of additional functional domains. Sorting nexin-20 (SNX20) and sorting nexin-21 (SNX21) comprise the SNX-PXB proteins. The presence of a predicted protein:protein interaction domain, termed the PX-associated B (PXB) domain, has led to the proposal that they function as endosome-associated scaffolds. Here we have used unbiased quantitative proteomics to define the SNX21 interactome. We reveal that SNX21's amino-terminal extension interacts with huntingtin (Htt) while the PXB domain appears to associate with septins, a family of cytoskeletal and membrane associated proteins. In establishing that these interactions are sufficient for SNX21 to recruit Htt and septins on to an endosomal population, we reveal a scaffolding function for this sorting nexin. Our work paves the way for a more detailed mechanistic analysis of the role(s) of the SNX-PXB proteins in endosomal biology.