Activating FcγR function depends on endosomal-signaling platforms
Samira Benadda,
Mathilde Nugue,
Despoina Koumantou,
Marcelle Bens,
Mariacristina De Luca,
Olivier Pellé,
Renato C. Monteiro,
Irini Evnouchidou,
Loredana Saveanu
Affiliations
Samira Benadda
INSERM U1149, CRI, Centre de Recherche sur l'Inflammation, Paris, France; CNRS ERL8252, Paris, France; Université de Paris, Site Xavier Bichat, Paris, France; Inflamex Laboratory of Excellence, Paris, France
Mathilde Nugue
INSERM U1149, CRI, Centre de Recherche sur l'Inflammation, Paris, France; CNRS ERL8252, Paris, France; Université de Paris, Site Xavier Bichat, Paris, France; Inflamex Laboratory of Excellence, Paris, France
Despoina Koumantou
INSERM U1149, CRI, Centre de Recherche sur l'Inflammation, Paris, France; CNRS ERL8252, Paris, France; Université de Paris, Site Xavier Bichat, Paris, France; Inflamex Laboratory of Excellence, Paris, France
Marcelle Bens
INSERM U1149, CRI, Centre de Recherche sur l'Inflammation, Paris, France; CNRS ERL8252, Paris, France; Université de Paris, Site Xavier Bichat, Paris, France; Inflamex Laboratory of Excellence, Paris, France
Mariacristina De Luca
INSERM U1149, CRI, Centre de Recherche sur l'Inflammation, Paris, France; CNRS ERL8252, Paris, France; Université de Paris, Site Xavier Bichat, Paris, France; Inflamex Laboratory of Excellence, Paris, France
Olivier Pellé
INSERM UMR 1163, Cell Sorting Facility, Paris, France; INSERM UMR 1163, Laboratoire of Immunogenetics of Pediatric Autoimmunity, Paris, France
Renato C. Monteiro
INSERM U1149, CRI, Centre de Recherche sur l'Inflammation, Paris, France; CNRS ERL8252, Paris, France; Université de Paris, Site Xavier Bichat, Paris, France; Inflamex Laboratory of Excellence, Paris, France
Irini Evnouchidou
INSERM U1149, CRI, Centre de Recherche sur l'Inflammation, Paris, France; CNRS ERL8252, Paris, France; Université de Paris, Site Xavier Bichat, Paris, France; Inflamex Laboratory of Excellence, Paris, France; Inovarion, Paris, France; Corresponding author
Loredana Saveanu
INSERM U1149, CRI, Centre de Recherche sur l'Inflammation, Paris, France; CNRS ERL8252, Paris, France; Université de Paris, Site Xavier Bichat, Paris, France; Inflamex Laboratory of Excellence, Paris, France; Corresponding author
Summary: Cell surface receptor internalization can either terminate signaling or activate alternative endosomal signaling pathways. We investigated here whether endosomal signaling is involved in the function of the human receptors for Fc immunoglobulin fragments (FcRs): FcαRI, FcγRIIA, and FcγRI. All these receptors were internalized after their cross-linking with receptor-specific antibodies, but their intracellular trafficking was different. FcαRI was targeted directly to lysosomes, while FcγRIIA and FcγRI were internalized in particular endosomal compartments described by the insulin responsive aminopeptidase (IRAP), where they recruited signaling molecules, such as the active form of the kinase Syk, PLCγ and the adaptor LAT. Destabilization of FcγR endosomal signaling in the absence of IRAP compromised cytokine secretion downstream FcγR activation and macrophage ability to kill tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Our results indicate that FcγR endosomal signaling is required for the FcγR-driven inflammatory reaction and possibly for the therapeutic action of monoclonal antibodies.
