Posttranslational activation of bone morphogenetic protein 2 is mediated by proprotein convertase 6 during decidualization for pregnancy establishment.
Bone morphogenetic proteins (BMPs) require major posttranslational modifications to become biologically active. One such key modification is endoproteolytic cleavage of the initially synthesized nonactive precursor protein to release the mature ligand. Here we show in a physiological context of uterine stromal decidualization that BMP2 cleavage is mediated by proprotein convertase 5/6 (PC6). Decidualization is a uterine remodeling event critical for embryo implantation. Deletion or knockdown of either BMP2 or PC6 inhibits decidualization causing implantation failure and female infertility. In this study we provide biochemical and physiological evidence that PC6 proteolytically activates BMP2. We used freshly isolated primary human endometrial stromal cells and demonstrated that PC6 was the sole member of the PC family significantly up-regulated during decidualization. The precursor form of BMP2 was reduced, whereas its active form was increased during decidualization. Inhibition of PC6 activity inhibited decidualization, and this was accompanied by a total blockade of BMP2 activation. Addition of recombinant active BMP2 partially rescued the decidualization arrest caused by PC6 inhibition. PC6 processed BMP2 at the KREKR(282) downward arrow cleavage site, and mutating this site prevented the cleavage. This study thus demonstrates for the first time that the proteolytic activation and thus bioavailability of BMP2 is controlled by PC6.
Heng
Sophea
S
Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia.
Paule
Sarah
S
Hardman
Belinda
B
Li
Ying
Y
Singh
Harmeet
H
Rainczuk
Adam
A
Stephens
Andrew N
AN
Nie
Guiying
G
D000595:Amino Acid Sequence; D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D010064:Embryo Implantation / Q000235:genetics / Q000502:physiology*; D004717:Endometrium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005452:Fluoresceins / Q000494:pharmacology; D006801:Humans; D011247:Pregnancy; D011255:Pregnancy Maintenance / Q000235:genetics / Q000502:physiology; D045702:Proprotein Convertase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics; D054928:Validation Studies as Topic
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D004791:Enzyme Inhibitors; D005452:Fluoresceins; C024098:6-carboxyfluorescein; D045702:Proprotein Convertase 5