Phosphorylation on serine 72 modulates Rab7A palmitoylation and retromer recruitment.

Rab7A has a key role in regulating membrane trafficking at late endosomes. By interacting with several different effectors, this small GTPase controls late endosome mobility, orchestrates fusion events between late endosomes and lysosomes, and participates in the formation of and regulates the fusion between autophagosomes and lysosomes. Rab7A is also responsible for the spatiotemporal recruitment of retromer, which is required for the endosome-to-trans-Golgi network retrieval of cargo receptors such as sortilin (SORT1) and CI-MPR (also known as IGF2R). Recently, several post-translational modifications have been shown to modulate Rab7A functions, including palmitoylation, ubiquitination and phosphorylation. Here, we show that phosphorylation of Rab7A at serine 72 is important to modulate its interaction with retromer, as the non-phosphorylatable Rab7AS72A mutant is not able to interact with and recruit retromer to late endosomes. We have previously shown that Rab7A palmitoylation is also required for efficient retromer recruitment. We found that palmitoylation of Rab7AS72A is reduced compared to that of the wild-type protein, suggesting an interplay between S72 phosphorylation and palmitoylation in regulating the Rab7A-retromer interaction. Finally, we identify NEK7 as a kinase required to phosphorylate Rab7A to promote retromer binding and recruitment.