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Vol. 19, Issue 1, 414-423, January 2008

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Ca²⁺-dependent Calmodulin Binding to FcRn Affects Immunoglobulin G Transport in the Transcytotic Pathway

Bonny L. Dickinson^*,, Steven M. Claypool, June A. D'Angelo^*,, Martha L. Aiken^*,, Nanda Venu, Elizabeth H. Yen, Jessica S. Wagner^,||, Jason A. Borawski, Amy T. Pierce^*,, Robert Hershberg^¶, Richard S. Blumberg^,||, and Wayne I. Lencer^,||

*The Research Institute for Children, Children's Hospital, Department of Pediatrics, New Orleans, LA 70118; Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Science Center, New Orleans, LA 70112; Division of Gastroenterology, Brigham and Women's Hospital and the Department of Medicine, Harvard Medical School, Boston, MA 02115; Gastrointestinal Cell Biology, Division of Pediatric Gastroenterology and Nutrition, Children's Hospital and the Department of Pediatrics, Harvard Medical School, Boston, MA 02115; ^¶Department of Medicine and Medical Genetics, University of Washington School of Medicine, Seattle, WA 98112; and ^||Harvard Digestive Diseases Center, Boston, MA 02115

Submitted July 11, 2007; Revised October 9, 2007; Accepted November 2, 2007
Monitoring Editor: Keith Mostov

The Fc receptor FcRn transports immunoglobulin G (IgG) so as to avoid lysosomal degradation and to carry it bidirectionally across epithelial barriers to affect mucosal immunity. Here, we identify a calmodulin-binding site within the FcRn cytoplasmic tail that affects FcRn trafficking. Calmodulin binding to the FcRn tail is direct, calcium-dependent, reversible, and specific to residues comprising a putative short amphipathic -helix immediately adjacent to the membrane. FcRn mutants with single residue substitutions in this motif, or FcRn mutants lacking the cytoplasmic tail completely, exhibit a shorter half-life and attenuated transcytosis. Chemical inhibitors of calmodulin phenocopy the mutant FcRn defect in transcytosis. These results suggest a novel mechanism for regulation of IgG transport by calmodulin-dependent sorting of FcRn and its cargo away from a degradative pathway and into a bidirectional transcytotic route.

Address correspondence to: Wayne I. Lencer (wayne.lencer{at}childrens.harvard.edu)

Abbreviations used: β2m, β-2-microglobulin; CaM, calmodulin; CaM-Seph, calmodulin-Sepharose; GST, glutathione transferase; HA, influenza hemagglutinin epitope; Ig, immunoglobulin; mAb, monoclonal antibody; MDCK, Madin-Darby canine kidney; NIP, 5-iodo-4-hydroxy-3-nitrophenylacetyl.

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