Ca2+-dependent calmodulin binding to FcRn affects immunoglobulin G transport in the transcytotic pathway.
The Fcgamma 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 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.
Dickinson
Bonny L
BL
The Research Institute for Children, Children's Hospital, Department of Pediatrics, New Orleans, LA 70118, USA.
Claypool
Steven M
SM
D'Angelo
June A
JA
Aiken
Martha L
ML
Venu
Nanda
N
Yen
Elizabeth H
EH
Wagner
Jessica S
JS
Borawski
Jason A
JA
Pierce
Amy T
AT
Hershberg
Robert
R
Blumberg
Richard S
RS
Lencer
Wayne I
WI
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D016764:Cell Polarity; D004285:Dogs; D004705:Endocytosis; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011961:Receptors, Fc / Q000737:chemistry / Q000378:metabolism*
D002147:Calmodulin; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D002118:Calcium; C100688:Fc receptor, neonatal