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MBC in Press, published online ahead of print November 14, 2007
Mol. Biol. Cell 10.1091/mbc.E07-07-0658

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Submitted on July 11, 2007
Revised on October 9, 2007
Accepted on November 2, 2007

Ca2+-dependent Calmodulin-binding to FcRn Affects IgG Transport in the Transcytotic Pathway

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

*The Research Institute for Children, Children’s Hospital, Department of Pediatrics, New Orleans, LA 70118; {dagger}Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Science Center, New Orleans, LA 70112; {ddagger}Division of Gastroenterology, Brigham and Women’s Hospital and the Department of Medicine, Harvard Medical School, Boston, MA 02115; {sect}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; ||Harvard Digestive Diseases Center, Boston, MA 02115

Monitoring Editor: Keith Mostov

The Fc{gamma} receptor FcRn transports 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 {alpha}-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)




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