Divergent Intracellular Sorting of FcγRIIA and FcγRIIB2

The human low affinity Fc gamma RII family includes both the activating receptor Fc gamma RIIA and the inhibitory receptor Fc gamma RIIB2. These receptors have opposing signaling functions but are both capable of internalizing IgG-containing immune complexes through clathrin-mediated endocytosis. We demonstrate that upon engagement by multivalent aggregated human IgG, Fc gamma RIIA expressed in ts20 Chinese hamster fibroblasts is delivered along with its ligand to lysosomal compartments for degradation, while Fc gamma RIIB2 dissociates from the ligand and is routed separately into the recycling pathway. Fc gamma RIIA sorting to lysosomes requires receptor multimerization, but does not require either Src family kinase activity or ubiquitylation of receptor lysine residues. The sorting of Fc gamma RIIB2 away from a degradative fate is not due to its lower affinity for IgG and occurs even upon persistent receptor aggregation. Upon co-engagement of Fc gamma RIIA and Fc gamma RIIB2, the receptors are sorted independently to distinct final fates after dissociation of co-clustering ligand. These results reveal fundamental differences in the trafficking behavior of different Fc gamma receptors.