A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking

Abstract

The cation‐independent mannose‐6‐phosphate receptor (CI‐MPR) follows a highly regulated sorting itinerary to deliver hydrolases from the trans‐Golgi network (TGN) to lysosomes. Cycling of CI‐MPR between the TGN and early endosomes is mediated by GGA3, which directs TGN export, and PACS‐1, which directs endosome‐to‐TGN retrieval. Despite executing opposing sorting steps, GGA3 and PACS‐1 bind to an overlapping CI‐MPR trafficking motif and their sorting activity is controlled by the CK2 phosphorylation of their respective autoregulatory domains. However, how CK2 coordinates these opposing roles is unknown. We report a CK2‐activated phosphorylation cascade controlling PACS‐1‐ and GGA3‐mediated CI‐MPR sorting. PACS‐1 links GGA3 to CK2, forming a multimeric complex required for CI‐MPR sorting. PACS‐1‐bound CK2 stimulates GGA3 phosphorylation, releasing GGA3 from CI‐MPR and early endosomes. Bound CK2 also phosphorylates PACS‐1Ser₂₇₈, promoting binding of PACS‐1 to CI‐MPR to retrieve the receptor to the TGN. Our results identify a CK2‐controlled cascade regulating hydrolase trafficking and sorting of itinerant proteins in the TGN/endosomal system.