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Filamin A Stabilizes FcRI Surface Expression and Prevents Its Lysosomal Routing¹

Jeffrey M. Beekman^2,*, Cees E. van der Poel^2,*, Joke A. van der Linden^*, Debbie L. C. van den Berg^*, Peter V. E. van den Berghe^*, Jan G. J. van de Winkel^*, and Jeanette H. W. Leusen^3,*

^* Immunotherapy Laboratory, Department of Immunology, University Medical Center, and Genmab, Utrecht, The Netherlands

Filamin A, or actin-binding protein 280, is a ubiquitously expressed cytosolic protein that interacts with intracellular domains of multiple receptors to control their subcellular distribution, and signaling capacity. In this study, we document interaction between FcRI, a high-affinity IgG receptor, and filamin A by yeast two-hybrid techniques and coimmunoprecipitation. Both proteins colocalized at the plasma membrane in monocytes, but dissociated upon FcRI triggering. The filamin-deficient cell line M2 and a filamin-reconstituted M2 subclone (A7), were used to further study FcRI-filamin interactions. FcRI transfection in A7 cells with filamin resulted in high plasma membrane expression levels. In filamin-deficient M2 cells and in filamin RNA-interference studies, FcRI surface expression was consistently reduced. FcRI localized to LAMP-1-positive vesicles in the absence of filamin as shown by confocal microscopy indicative for lysosomal localization. Mouse IgG2a capture experiments suggested a transient membrane expression of FcRI before being transported to the lysosomes. These data support a pivotal role for filamin in FcRI surface expression via retention of FcRI from a default lysosomal pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Medarex Europe (to J.M.B.) and Dutch Science Foundation Grant NWO/ALW 07764 (to C.E.v.d.P.).

² J.M.B. and C.E.v.d.P. contributed equally to this manuscript.

³ Address correspondence and reprint requests to Dr. Jeanette H. W. Leusen, Department of Immunology, University Medical Center, Lundlaan 6, Utrecht, 3584 EA, The Netherlands. E-mail address: J.H.W.Leusen{at}umcutrecht.nl

⁴ Abbreviations used in this paper: CY, cytoplasmic tail; siRNA, short interfering RNA; NP40, Nonidet P-40; ER, endoplasmatic reticulum; EEA-1, early endosomal Ag-1; LAMP, lysosomal-associated membrane protein.

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