Cleavage of endometrial alpha-integrins into their functional forms is mediated by proprotein convertase 5/6.
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Paule S, Aljofan M, Simon C, Rombauts LJ, Nie G
Cleavage of endometrial alpha-integrins into their functional forms is mediated by proprotein convertase 5/6.
Hum Reprod. 2012 Sep;27(9):2766-74. doi: 10.1093/humrep/des203. Epub 2012 Jun 26.
- PubMed ID
- 22740495 [ View in PubMed]
- Abstract
BACKGROUND: Proprotein convertases (PCs) post-translationally activate a large number of protein precursors through limited cleavage. PC5/6 (PC6) in the human endometrium is tightly regulated during receptivity for embryo implantation. Integrins are transmembrane glycoproteins, some of which play an important role in the adhesive interactions between the trophoblast (blastocyst) and uterine epithelium at implantation. Integrins require PC cleavage for post-translational modification. We hypothesize that pro-integrin-alphas in the endometrial epithelium are post-translationally cleaved by PC6 into functional subunits for the binding of blastocyst and adhesion of extracellular matrix proteins. METHODS AND RESULTS: We first used the endometrial epithelial cell line, HEC1A, into which siRNA specific to human PC6 (PC6-siRNA) or scrambled sequence (control) was stably transfected. The specific knockdown was confirmed by real-time RT-PCR. PC6-siRNA cells reduced their capacity to attach to trophoblast spheroids and bind to fibronectin compared with control. Knockdown of PC6 decreased cell surface presentation of functional integrins-alpha1, alpha2, alpha5, alphaV and alphaVbeta5. Western blot analysis demonstrated that PC6 was responsible for the post-translational cleavage of pro-integrin-alpha5 and integrin-alphaV into their heavy and light chains in HEC1A cells. We then isolated primary human endometrial epithelial cells and validated that PC6 mediated the post-translational cleavage of integrin-alphas in these cells. CONCLUSIONS: This study implicates PC6 as a key regulatory protein essential for the attachment of the blastocyst to the endometrial epithelium through the processing of pro-integrin-alphas. Compromised PC6 action reduces the post-translational modification of integrin-alphas, thus compromising implantation.