High affinity FcγR activating function depends on IRAP+ endosomal-signaling platforms

Although endocytosis of cell surface receptors is generally thought to terminate the signaling, for some receptors, endocytosis sustains signaling. We wondered if endosomal signaling participates to the function of the receptors for Fc immunoglobulin fragments (FcRs) that are highly internalized after their activation. We demonstrate here that four different FcRs follow distinct endocytic pathways after activation. While FcRI is internalized into lysosomes, Fc{gamma}RIIA is internalized and partially retained in early endosomes, whereas the inhibitory receptor Fc{gamma}RIIB is internalized in endosomes decorated by the autophagy marker LC3. Interestingly, the high affinity Fc{gamma}RI is internalized in specialized endosomal compartments described by the Insulin Responsive AminoPeptidase (IRAP), where it remains associated with the active form of the signaling kinase Syk. Our results show that Fc{gamma}RI has the ability to build endosomal-signaling platforms, which depend on the presence of IRAP and Rab14. Destabilization of the endosomal signaling platforms compromised the ability of peritoneal macrophages to kill tumor cells by antibody-dependent cell mediated cytotoxicity, indicating that Fc{gamma}RI endosomal signaling is required for the therapeutic action of anti-tumor monoclonal antibodies. One sentence summaryBinding of immune complexes to Fc{gamma}RI receptor leads to receptor internalization and sustained signaling from endosomes described by the Insulin Responsive AminoPeptidase and the small GTPase Rab14.