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Posttranslational removal of α‐dystroglycan N terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women
Author(s) -
Heng Sophea,
Paule Sarah G.,
Li Ying,
Rombauts Luk J.,
Vollenhoven Beverley,
Salamonsen Lois A.,
Nie Guiying
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-269456
Subject(s) - embryo , dystroglycan , endometrium , cleavage (geology) , microbiology and biotechnology , chemistry , andrology , cell , biology , endocrinology , medicine , biochemistry , laminin , paleontology , fracture (geology)
Embryo implantation requires a healthy embryo and a receptive endometrium (inner lining of the uterus); endometrial receptivity acquisition involves considerable epithelial surface remodeling. Dystroglycan (DG), a large cell surface glycoprotein, consists of α‐ and β‐subunits; β‐DG anchors within the plasma membrane whereas α‐DG attaches extracellularly to β‐DG. The glycosylated central α‐DG mediates adhesion, but it is obstructed by its large N terminus (α‐DG‐N); α‐DG‐N removal enables DG's adhesive function. We demonstrate here that full‐length α‐DG in the human endometrial epithelium is a barrier for embryo attachment and that removal of α‐DG‐N by proprotein convertase 5/6 (PC6; a protease critical for implantation) regulates receptivity. This was evidenced by: 1) α‐DG contains a PC6‐cleavage site near α‐DG‐N, and PC6 cleaves a peptide harboring such a site; 2) PC6 knockdown reduces α‐DG‐N removal from endometrial epithelial cell surface and blastocyst adhesion; 3) mutating the PC6‐cleavage site prevents α‐DG‐N removal, causing cell surface retention of full‐length α‐DG and loss of adhesiveness; 4) α‐DG‐N is removed from endometrial tissue in vivo for receptivity and uterine fluid α‐DG‐N reflects tissue removal and receptivity. We thus identified α‐DG‐N removal as an important posttranslational control of endometrial receptivity and uterine fluid α‐DG‐N as a potential biomarker for receptivity in women.—Heng, S., Paule, S. G., Li, Y., Rombauts, L. J., Vollenhoven, B., Salamonsen, L. A., Nie, G. Posttranslational removal of α‐dystroglycan N terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women. FASEB J. 29, 4011‐4022 (2015). www.fasebj.org