Ectodomain shedding of Fcalpha receptor is mediated by ADAM10 and ADAM17.
FcalphaR (CD89) plays important roles in immunoglobulin A (IgA)-mediated immune responses. Soluble forms of FcalphaR (sFcalphaR) are found in the culture supernatants of FcalphaR-expressing cells, in human serum and in the serum of FcalphaR transgenic mice, and have been suggested to be produced through a proteolytic process. However, little is known about the mechanism involved in the proteolytic release of sFcalphaR. In this study, we investigated the shedding mechanism of FcalphaR and determined the nature of the proteinase involved in FcalphaR shedding. In chemical inhibitor assays, shedding of FcalphaR was dramatically inhibited by EDTA, EGTA and a broad-spectrum metalloproteinase inhibitor, GM6001, suggesting that a metalloproteinase was responsible for FcalphaR shedding. Overexpression of dominant-negative mutants of ADAM (a disintegrin and metalloproteinase) 10 and ADAM17 markedly inhibited the production of sFcalphaR. Finally, knockdown of both endogenous ADAM10 and endogenous ADAM17 inhibited FcalphaR shedding, demonstrating that ADAM10 and ADAM17 were involved in the shedding of FcalphaR. The characterization of ADAM10 and ADAM17 as sFcalphaR-releasing enzymes provides a novel insight into the molecular mechanism of sFcalphaR production and will help in further elucidation of the physiological and pathological roles of sFcalphaR.
Peng
Min
M
Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Guo
Sha
S
Yin
Na
N
Xue
Jing
J
Shen
Lian
L
Zhao
Qing
Q
Zhang
Wei
W
D051722:ADAM Proteins / Q000276:immunology / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D020298:U937 Cells
D008565:Membrane Proteins; D017455:Receptors, IgE; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse