Cleavage of endometrial α-integrins into their functional forms is mediated by proprotein convertase 5/6

Sarah G Paule, Mohamad Aljofan, Carlos Simon, Luk Rombauts, Guiying Nie

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

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-as 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-a1, a2, a5, aV and aVb5. Western blot analysis demonstrated that PC6 was responsible for the post-translational cleavage of pro-integrin-a5 and integrin-aV 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-as 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-as. Compromised PC6 action reduces the post-translational modification of integrin-as, thus compromising implantation.
Original languageEnglish
Pages (from-to)2766 - 2774
Number of pages9
JournalHuman Reproduction
Volume27
Issue number9
DOIs
Publication statusPublished - 2012

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