High-temperature requirement protein A4 (HtrA4) suppresses the fusogenic activity of syncytin-1 and promotes trophoblast invasion.
Cell-cell fusion and cell invasion are essential for placental development. Human cytotrophoblasts in the chorionic villi may undergo cell-cell fusion to form syncytiotrophoblasts to facilitate nutrient-gas exchange or differentiate into extravillous trophoblasts (EVTs) to facilitate maternal-fetal circulation. The placental transcription factor glial cells missing 1 (GCM1) regulates syncytin-1 and -2 expression to mediate trophoblast fusion. Interestingly, GCM1 and syncytin-1 are also expressed in EVTs with unknown physiological functions. In this study, we performed chromatin immunoprecipitation-on-chip (ChIP-chip) analysis and identified the gene for high-temperature requirement protein A4 (HtrA4) as a GCM1 target gene, which encodes a serine protease facilitating cleavage of fibronectin and invasion of placental cells. Importantly, HtrA4 is immunolocalized in EVTs at the maternal-fetal interface, and its expression is decreased by hypoxia and in preeclampsia, a pregnancy complication associated with placental hypoxia and shallow trophoblast invasion. We further demonstrate that HtrA4 interacts with syncytin-1 and suppresses cell-cell fusion. Therefore, HtrA4 may be crucial for EVT differentiation by playing a dual role in prevention of cell-cell fusion of EVTs and promotion of their invasion into the uterus. Our study reveals a novel function of GCM1 and HtrA4 in regulation of trophoblast invasion and that abnormal HrtA4 expression may contribute to shallow trophoblast invasion in preeclampsia.
Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
Liang-Jie
LJ
Wang
Mei-Leng
ML
Cheong
Yun-Shien
YS
Lee
Ming-Ting
MT
Lee
Hungwen
H
Chen
D002454:Cell Differentiation; D002459:Cell Fusion; D015687:Cell Hypoxia; D002460:Cell Line; D002465:Cell Movement; D002824:Chorionic Villi / Q000378:metabolism; D004268:DNA-Binding Proteins; D005260:Female; D015686:Gene Products, env / Q000378:metabolism; D057809:HEK293 Cells; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism / Q000502:physiology*; D010929:Placentation; D011225:Pre-Eclampsia / Q000378:metabolism; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014327:Trophoblasts / Q000502:physiology*
D004268:DNA-Binding Proteins; C491089:GCM1 protein, human; D015686:Gene Products, env; D009687:Nuclear Proteins; D011257:Pregnancy Proteins; D014157:Transcription Factors; C405335:syncytin; C576189:HtrA4 protein, human; D057057:Serine Proteases; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases