title: Caspase-14 suppresses GCM1 acetylation and inhibits placental cell differentiation.
abstract: Glial cell missing 1 (GCM1) transcription factor regulates placental cell fusion into the syncytiotrophoblast. Caspase-14 is proteolytically activated to mediate filaggrin processing during keratinocyte differentiation. Interestingly, altered expression of nonactivated caspase-14 proenzyme is associated with tumorigenesis and diabetic retinopathy, suggesting that caspase-14 may perform physiological functions independently of its protease activity. Here, we performed tandem affinity purification coupled with mass spectrometry analysis to identify caspase-14 proenzyme as a GCM1-interacting protein that suppresses GCM1 activity and syncytiotrophoblast differentiation. Immunohistochemistry revealed that caspase-14 and GCM1 colocalize to placental cytotrophoblast cells at 8 wk of gestation and syncytiotrophoblast layer at term. Further, we demonstrated that caspase-14 mRNA level is decreased by 40% in placental BeWo cells treated with forskolin (FSK). To the contrary, stimulation of GCM1-regulated placental cell fusion and human chorionic gonadotropin β (hCGβ) expression by FSK is enhanced by caspase-14 knockdown. Indeed, GCM1 protein level is increased by 40% in the caspase-14-knockdown BeWo cells. Because GCM1 is stabilized by acetylation, we subsequently showed that caspase-14 impedes the interaction between GCM1 and cAMP response element-binding protein (CREB)-binding protein (CBP) to suppress CBP-mediated acetylation and transcriptional coactivation of GCM1. Therefore, caspase-14 can suppress placental cell differentiation through down-regulation of GCM1 activity.
authors.affiliation: Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Wu
authors.forename: Hsiao-Fan
authors.initials: HF
authors.lastname: Lo
authors.forename: Sih-Han
authors.initials: SH
authors.lastname: Chen
authors.forename: Hungwen
authors.initials: H
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D050882:CREB-Binding Protein / Q000378:metabolism; D053456:Caspase 14 / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004268:DNA-Binding Proteins; D005260:Female; D000091344:Filaggrin Proteins; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D010929:Placentation; D011247:Pregnancy; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C491089:GCM1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D005576:Colforsin; D050882:CREB-Binding Protein; D053456:Caspase 14
keywords: CBP; cell-cell fusion; syncytiotrophoblast