Direct interaction between FcγRI (CD64) and periplakin controls receptor endocytosis and ligand binding capacity

doi:10.1073/pnas.0401217101

Direct interaction between FcγRI (CD64) and periplakin controls receptor endocytosis and ligand binding capacity

^*Immunotherapy Laboratory, Department of Immunology, and ^†Medarex Europe, University Medical Center Utrecht, 3584 EA, Utrecht, The Netherlands; and ^‡Genmab, Yalelaan 60, 3584 CM, Utrecht, The Netherlands

Edited by Jonathan W. Uhr, University of Texas Southwestern Medical Center, Dallas, TX, and approved May 24, 2004 (received for review February 20, 2004)

Abstract

FcγRI depends for its biological function on both the intracellular domain of the α-chain and associated Fc receptor (FcR) γ-chains. However, functional protein effectors of FcγRI's intracellular domain have not been identified. In this study, we identified periplakin (PPL) as a selective interacting protein for the intracellular tail of FcγRI but no other activatory FcRs. The interaction was confirmed by coimmunoprecipitation and blot-overlay assays. PPL and FcγRI colocalized at the plasma membrane in monocytes and cell transfectants, and both were up-regulated by IFN-γ. By expressing C-terminal PPL in transfectants, we established a pivotal role for this protein in FcγRI ligand binding, endocytosis, and antigen presentation. These data illustrate that intracellular protein interactions with a multisubunit FcR α-chain can confer unique properties to the receptor.

Footnotes

↵ ¶ To whom correspondence should be addressed at: Department of Immunology, Lundlaan 6, University Medical Center Utrecht, 3584 EA, Utrecht, The Netherlands. E-mail: j.h.w.leusen{at}lab.azu.nl.
↵ § J.G.J.v.d.W. and J.H.W.L. contributed equally to this work.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: CY, cytosolic domain; EA, erythrocyte–antibody; FcR, Fc receptor; fl, full-length; m, murine; OVA, ovalbumin; PPL, periplakin; RIPA, radioimmunoprecipitation assay.