PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic

PACS-1 is a cytosolic protein involved in controlling the correct subcellul ar localization of integral membrane proteins that contain acidic cluster s orting motifs, such as furin and human immunodeficiency virus type 1 (HIV-1 ) Nef. We have now investigated the interaction of PACS-1 with heterotetram eric adaptor complexes. PACS-1 associates with both AP-1 and AP-3, but not AP-2, and forms a ternary complex between furin and AP-1. A short sequence within PACS-1 that is essential for binding to AP-1 has been identified. Mu tation of this motif yielded a dominant-negative PACS-1 molecule that can s till bind to acidic cluster motifs on cargo proteins but not to adaptor com plexes. Expression of dominant-negative PACS-1 causes a mislocalization of both furin and mannose 6-phosphate receptor from the trans-Goigi network, b ut has no effect on the localization of proteins that do not contain acidic cluster sorting motifs. Furthermore, expression of dominant-negative PACS- 1 inhibits the ability of HIV-1 Nef to downregulate MHC-I. These studies de monstrate the requirement for PACS-1 interactions with adaptor proteins in multiple processes, including secretory granule biogenesis and HIV-1 pathog enesis.