Annexin-A5 organized in 2D-network at the plasmalemma eases human trophoblast fusion

Abstract

Only a limited number of human cells can fuse to form a multinucleated syncytium. Cell fusion occurs as part of the differentiation of some cell types, including myotubes in muscle and osteoclasts in remodeling bone. In the differentiation of the human placenta, mononuclear cytotrophoblasts aggregate and fuse to form endocrinologically active, non-proliferative, multinucleated syncytia. These syncytia allow the exchange of nutrients and gases between the maternal and fetal circulation. Alteration of syncytial formation during pregnancy affects fetal growth and the outcome of the pregnancy. Here, we demonstrate the role of annexin A5 (AnxA5) in syncytial formation by cellular delivery of recombinant AnxA5 and RNA interference. By a variety of co-immunoprecipitation, immunolocalization and proximity experiments, we show that a pool of AnxA5 organizes at the inner-leaflet of the plasma membrane in the vicinity of a molecular complex that includes E-Cadherin, α-Catenin and β-Catenin, three proteins previously shown to form adherens junctions implicated in cell fusion. A combination of knockdown and reconstitution experiments with AnxA5, with or without the ability to self-assemble in 2D-arrays, demonstrate that this AnxA5 2D-network mediates E-Cadherin mobility in the plasmalemma that triggers human trophoblasts aggregation and thereby cell fusion.

Interactions with Muscle Cells Boost Fusion, Stemness, and Drug Resistance of Prostate Cancer Cells

“…We found that coculturing of cancer and muscle cells boosts the expression levels of Syn1 and AnxA5, proteins associated with several fusion processes (4,6,7,30). The coculturing with hMYOs increased levels of Syn1 and AnxA5 gene expression ( Fig.…”

“…Numbers of viable PC3 cells after a 24-hour application of the drug were normalized to the numbers in corresponding controls not treated with the drug. PC3 cells (1); PC3 cells grown in the presence of either Syn1 peptide (3) or scrambled Syn1 peptide (2); PC3 cells cocultured in a direct contact with hMYOs (4), PC3 cells cocultured with hMYOs in the presence of either Syn1 peptide (6) or scrambled Syn1 peptide (5). All results are shown as means AE SEM (n !…”

“…Several proteins, including annexin A5 (AnxA5) and syncytin 1 (Syn1), have been implicated in diverse fusion processes. AnxA5 is involved in myoblast fusion (4), osteoclast fusion (5), and in placental trophoblast fusion (6). Syn1, a captive retroviral envelope protein that acquires a functional conformation after interactions with the ubiquitous receptor ASCT2, has been implicated in placental trophoblast fusion (7) and osteoclast fusion (5,8).…”

Calcium Regulates the Nuclear Localization of Protein Arginine Deiminase 2

“…The small GTPase Ran, which plays an important role in nucleocytoplasmic shuttling, 28,29 showed a high L/H ratio in all three data sets. By contrast, the cytoplasmic protein ANXA5 [30][31][32] had a high L/H ratio only in the BioID2 and BioID2PAD2 comparison ( Figure 3C left panel). The L/H ratio of FXR1, which localizes in the nucleus, [33][34][35] increased in the presence of calcium, consistent with our finding that calcium triggers the entry of PAD2 into the nucleus.…”

Conserved pathway activation following xenogeneic, heterotypic fusion

“…Homotypic fusion typically represents the final steps of cell maturation; and therefore, cells must often reach a certain differentiation state to achieve fusion. For example, it was recently shown that trophoblast fusion requires the assembly of a matrix of annexin A5 at the plasma membrane, a process that only occurs in later stages of maturation, to facilitate cell aggregation as a prerequisite for fusion (12). The resultant syncytiotrophoblast is a tremendous and essential benefit for the placenta because it effectively bars immune cells from the mother from invading the fetus and secretes large quantities of hormones needed to support pregnancy.…”