title: Posttranslational removal of α-dystroglycan N terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women.
abstract: 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.
authors.affiliation: *Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Sciences and Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia; Women's and Children's Programme, Monash Health, Clayton, Victoria, Australia; and Monash IVF, Clayton, Victoria, Australia.
authors.forename: Sophea
authors.initials: S
authors.lastname: Heng
authors.affiliation: *Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Sciences and Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia; Women's and Children's Programme, Monash Health, Clayton, Victoria, Australia; and Monash IVF, Clayton, Victoria, Australia.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Paule
authors.affiliation: *Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Sciences and Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia; Women's and Children's Programme, Monash Health, Clayton, Victoria, Australia; and Monash IVF, Clayton, Victoria, Australia.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: *Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Sciences and Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia; Women's and Children's Programme, Monash Health, Clayton, Victoria, Australia; and Monash IVF, Clayton, Victoria, Australia.
authors.forename: Luk J
authors.initials: LJ
authors.lastname: Rombauts
authors.affiliation: *Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Sciences and Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia; Women's and Children's Programme, Monash Health, Clayton, Victoria, Australia; and Monash IVF, Clayton, Victoria, Australia.
authors.forename: Beverley
authors.initials: B
authors.lastname: Vollenhoven
authors.affiliation: *Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Sciences and Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia; Women's and Children's Programme, Monash Health, Clayton, Victoria, Australia; and Monash IVF, Clayton, Victoria, Australia.
authors.forename: Lois A
authors.initials: LA
authors.lastname: Salamonsen
authors.affiliation: *Implantation and Placental Development Laboratory, Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Sciences and Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia; Women's and Children's Programme, Monash Health, Clayton, Victoria, Australia; and Monash IVF, Clayton, Victoria, Australia guiying.nie@hudson.org.au.
authors.forename: Guiying
authors.initials: G
authors.lastname: Nie
mesh_terms: D001755:Blastocyst / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism*; D010064:Embryo Implantation / Q000502:physiology*; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D045702:Proprotein Convertase 5 / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017434:Protein Structure, Tertiary; D059748:Proteolysis
chemical_list: C483081:DAG1 protein, human; D049030:Dystroglycans; D045702:Proprotein Convertase 5
keywords: adhesion molecule; biomarker; endometrium; glycoprotein; receptivity