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Receptor and Modulates Its Trafficking to Endosomal/Lysosomal Compartments1
,
* Laboratory of Immunology,
Virginia-Maryland Regional College of Veterinary Medicine, and
Department of Cell Biology and Molecular Genetics,
Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742;
¶ Laboratory of Cellular and Molecular Immunology and
|| T-Cell Tolerance and Memory Section, National Institutes of Health, Bethesda, MD 20892
The neonatal Fc receptor for IgG (FcRn) transfers maternal IgG to the offspring and protects IgG from degradation. The FcRn resides in an acidic intracellular compartment, allowing it to bind IgG. In this study, we found the association of FcRn and invariant chain (Ii). The interaction was initiated within the endoplasmic reticulum by Ii binding to either the FcRn H chain alone or FcRn H chain-β2-microglobulin complex and appeared to be maintained throughout the endocytic pathway. The CLIP in Ii was not required for FcRn-Ii association. The interaction was also detected in IFN-
-treated THP-1, epithelial and endothelial cells, and immature mouse DCs. A truncated FcRn without the cytoplasmic tail was unable to traffic to early endosomes; however, its location in early endosomes was restored by Ii expression. FcRn was also detected in the late endosome/lysosome only in the presence of Ii or on exposure to IFN-. In immature human or mouse DCs, FcRn was barely detected in the late endosome/lysosome in the absence of Ii. Furthermore, the cytoplasmic tail of Ii conferred tailless FcRn to route to both the early endosome and late endosome/lysosome in a hybrid molecule. Because the FcRn is expressed in macrophages and DCs or epithelial and endothelial cells where Ii is induced under inflammation and infection, these results reveal the complexity of FcRn trafficking in which Ii is capable of expanding the boundary of FcRn trafficking. Taken together, the intracellular trafficking of FcRn is regulated by its intrinsic sorting information and/or an interaction with Ii chain.
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1 This work was supported in part by National Institutes of Health Grants AI65892, AI67965, AI73139 (to X.Z.), N01-AO-6009 (to S.K.S.), and AI59617 (to W.S.); the faculty start-up package and Maryland Agricultural Experimental Station competitive grants from the University of Maryland (to X.Z.); and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Xiaoping Zhu, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, 8075 Greenmead Drive, College Park, MD 20742. E-mail address: xzhu1{at}umd.edu
3 Abbreviations used in this paper: FcRn, neonatal FcR; EEA1, early endosomal Ag-1; endo H, endo-N-acetylglucosaminidase; ER, endoplasmic reticulum; LAMP-1, lysosome-associated membrane glycoprotein-1; β2m, β2-microglobulin; TGN, trans-Golgi network; Ii, invariant chain; CHO, Chinese hamster ovary; HA, hemagglutinin; siRNA, small interfering RNA; BMDC, bone marrow-derived DC; TfR, transferrin receptor; TfR-GFP, GFP fusion of TfR; mFcRn, mouse FcRn; FcRn-Iicyt, a chimeric protein fusing the cytoplasmic tail of Ii to the extracellular domain of FcRn.
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  W. Mi, S. Wanjie, S.-T. Lo, Z. Gan, B. Pickl-Herk, R. J. Ober, and E. S. Ward Targeting the Neonatal Fc Receptor for Antigen Delivery Using Engineered Fc Fragments J. Immunol., December 1, 2008; 181(11): 7550 - 7561. [Abstract] [Full Text] [PDF]
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