Endosomal Microdomains: Retromer, ESCRT, and Their Cross-Regulation

The most fundamental function of an endosome is to sort cargo. The endosome field has expended tremendous effort to define and understand the peripheral membrane complexes that sort cargo, with one major advance anchored in the recognition that endosomal sorting complexes can define functional microdomains on the endosomal limiting membrane (Norris and Grant, 2020). Our studies were the first to develop an in vivo light microscopy-based system capable of reliably visualizing, measuring, and manipulating endosomal microdomains, taking advantage of the naturally large (1-5 micron diameter) endosomes of C. elegans coelomocyte cells (Fig. 4) (Norris et al., 2017). Our studies discovered for the first time that the recycling Retromer containing microdomains and degradative ESCRT containing microdomains on endosomes are distinct and cross-regulate—the RME-8 Hsc70-co-chaperone associates with SNX-1 in the recycling microdomain, preventing the assembly of degradative ESCRT-0 and clathrin within the recycling microdomain. Without RME-8, the microdomains mix and recycling cargo inappropriately degrades (Norris and Grant, 2017; Norris et al., 2020).

We also continue to define how RME-8 functions in this process by focusing on how the large and complex RME-8 protein itself functions. We recently combined AlphaFold structural predictions with in vivo mutation analysis of RME-8, advanced a new model in which SNX-1 and the RME-8 IWN domains control the oligomerization state of RME-8 and hence the productive exposure of the DNAJ domain for ESCRT-0 uncoating required for microdomain separation and successful retrograde recycling (Norris et al., 2022).