Highly glycosylated MUC1 mediates high affinity L-selectin binding at the human endometrial surface

Abstract

Background Sialyl-Lewis X/L-selectin high affinity binding interactions between transmembrane O-glycosylated mucins proteins and the embryo have been implicated in implantation processes within the human reproductive system. However, the adhesive properties of these mucins at the endometrial cell surface are difficult to resolve due to known discrepancies between in vivo models and the human reproductive system and a lack of sensitivity in current in vitro models. To overcome these limitations, an in vitro model of the human endometrial epithelial was interrogated with single molecule force spectroscopy (SMFS) to delineate the molecular configurations of mucin proteins that mediate the high affinity L-selectin binding required for human embryo implantation. Results This study reveals that MUC1 contributes to both the intrinsic and extrinsic adhesive properties of the HEC-1 cellular surface. High expression of MUC1 on the cell surface led to a significantly increased intrinsic adhesion force (148 pN vs. 271 pN, p < 0.001), whereas this adhesion force was significantly reduced (271 pN vs. 118 pN, p < 0.001) following siRNA mediated MUC1 ablation. Whilst high expression of MUC1 displaying elevated glycosylation led to strong extrinsic (> 400 pN) L-selectin binding at the cell surface, low expression of MUC1 with reduced glycosylation resulted in significantly less (≤200 pN) binding events. Conclusions An optimal level of MUC1 together with highly glycosylated decoration of the protein is critical for high affinity L-selectin binding. This study demonstrates that MUC1 contributes to cellular adhesive properties which may function to facilitate trophoblast binding to the endometrial cell surface through the L-selectin/sialyl-Lewis x adhesion system subsequent to implantation.

When the Embryo Meets the Endometrium: Identifying the Features Required for Successful Embryo Implantation

“…A widely proposed marker for endometrial receptivity is the high molecular weight transmembrane glycoprotein MUC1. MUC1 is a highly glycosylated protein whose expression in the luminal and glandular epithelium is regulated by progesterone and pro-inflammatory cytokines (i.e., TNF-α) [ 179 , 180 , 181 , 182 , 183 ]. While in other mammals MUC1 expression is down-regulated during the peri-implantation period in order to facilitate embryo attachment to the endometrium [ 184 , 185 , 186 ], in humans, its mRNA and protein levels increase during the secretory phase [ 151 , 152 ].…”

Recent Insights into Human Endometrial Peptidases in Blastocyst Implantation via Shedding of Microvesicles

“…Given that β 1-integrin is highly expressed in the decidua [32], APN/CD13 may be involved in implantation and/or invasion of blastocysts. Some alternative mechanisms of blastocyst attachment on the endometrial cell surface were shown as follows [49]: mucin1, a highly glycosylated polymeric protein contributes to cellular adhesive properties, which may function to facilitate blastocyst binding to the endometrial cell surface, but its action is through the L-selectin/sialyl-Lewis x adhesion system, and is not directly involved in binding between blastocyst and endometrial cells [50]. Integrins are transmembrane glycoproteins, which mediate cell-to-cell and cell-toextracellular matrix (ECM) adhesion.…”

Unique Tropism and Entry Mechanism of Mumps Virus

“…Although the expression of sLe x in normal human tissues is supposed to be very low, some clues indicate its expression in oral mucosa and breast tissues [ 56 ] and in heart, kidney, and lung tissues ( , 2 August 2021). sLe x is also found in highly glycosylated mucins and sphingolipids in their non-reducing terminal structures [ 57 ]. It had initially been recognized as a tumor-associated antigen by the monoclonal antibody CSLEX1, which reacts specifically with various tumor tissues [ 58 ].…”