Activatory and inhibitory Fcgamma receptors augment rituximab-mediated internalization of CD20 independent of signaling via the cytoplasmic domain.

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Vaughan AT, Chan CH, Klein C, Glennie MJ, Beers SA, Cragg MS

Activatory and inhibitory Fcgamma receptors augment rituximab-mediated internalization of CD20 independent of signaling via the cytoplasmic domain.

J Biol Chem. 2015 Feb 27;290(9):5424-37. doi: 10.1074/jbc.M114.593806. Epub 2015 Jan 7.

PubMed ID

25568316 [ View in PubMed

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Abstract

Type I anti-CD20 mAb such as rituximab and ofatumumab engage with the inhibitory FcgammaR, FcgammaRIIb on the surface of B cells, resulting in immunoreceptor tyrosine-based inhibitory motif (ITIM) phosphorylation. Internalization of the CD20.mAb.FcgammaRIIb complex follows, the rate of which correlates with FcgammaRIIb expression. In contrast, although type II anti-CD20 mAb such as tositumomab and obinutuzumab also interact with and activate FcgammaRIIb, this interaction fails to augment the rate of CD20.mAb internalization, raising the question of whether ITIM phosphorylation plays any role in this process. We have assessed the molecular requirements for the internalization process and demonstrate that in contrast to internalization of IgG immune complexes, FcgammaRIIb-augmented internalization of rituximab-ligated CD20 occurs independently of the FcgammaRIIb ITIM, indicating that signaling downstream of FcgammaRIIb is not required. In transfected cells, activatory FcgammaRI, FcgammaRIIa, and FcgammaRIIIa augmented internalization of rituximab-ligated CD20 in a similar manner. However, FcgammaRIIa mediated a slower rate of internalization than cells expressing equivalent levels of the highly homologous FcgammaRIIb. The difference was maintained in cells expressing FcgammaRIIa and FcgammaRIIb lacking cytoplasmic domains and in which the transmembrane domains had been exchanged. This difference may be due to increased degradation of FcgammaRIIa, which traffics to lysosomes independently of rituximab. We conclude that the cytoplasmic domain of FcgammaR is not required for promoting internalization of rituximab-ligated CD20. Instead, we propose that FcgammaR provides a structural role in augmenting endocytosis that differs from that employed during the endocytosis of immune complexes.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tositumomab	Low affinity immunoglobulin gamma Fc region receptor II-b	Protein	Humans	Unknown	Not Available	Details