title: Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2 in human IUGR.
abstract: Placental amino acid transport is decreased in intrauterine growth restriction (IUGR); however, the underlying mechanisms remain largely unknown. We have shown that mechanistic target of rapamycin (mTOR) signalling regulates system A amino acid transport by modulating the ubiquitination and plasma membrane trafficking of sodium-coupled neutral amino acid transporter 2 (SNAT-2) in cultured primary human trophoblast cells. We hypothesize that IUGR is associated with (1) inhibition of placental mTORC1 and mTORC2 signalling pathways, (2) increased amino acid transporter ubiquitination in placental homogenates and (3) decreased protein expression of SNAT-2 in the syncytiotrophoblast microvillous plasma membrane (MVM). To test this hypothesis, we collected placental tissue and isolated MVM from women with pregnancies complicated by IUGR (n=25) and gestational age-matched women with appropriately grown control infants (n=19, birth weights between the twenty-fifth to seventy-fifth percentiles). The activity of mTORC1 and mTORC2 was decreased whereas the protein expression of the ubiquitin ligase NEDD4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2; +72%, P<0.0001) and the ubiquitination of SNAT-2 (+180%, P<0.05) were increased in homogenates of IUGR placentas. Furthermore, IUGR was associated with decreased system A amino acid transport activity (-72%, P<0.0001) and SNAT-1 (-42%, P<0.05) and SNAT-2 (-31%, P<0.05) protein expression in MVM. In summary, these findings are consistent with the possibility that decreased placental mTOR activity causes down-regulation of placental system A activity by shifting SNAT-2 trafficking towards proteasomal degradation, thereby contributing to decreased fetal amino acid availability and restricted fetal growth in IUGR.
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A. Division of High-risk Pregnancy, Department of Obstetrics & Gynecology, Mackay Memorial Hospital, Taipei 10449, Taiwan yi-yung.chen@ucdenver.edu.
authors.forename: Yi-Yung
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A.
authors.forename: Fredrick J
authors.initials: FJ
authors.lastname: Rosario
authors.affiliation: Children's Health Research Institute, University of Western Ontario, London, Ontario N6C 2V5, Canada.
authors.forename: Majida Abu
authors.initials: MA
authors.lastname: Shehab
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A. Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Powell
authors.affiliation: Children's Health Research Institute, University of Western Ontario, London, Ontario N6C 2V5, Canada Department of Pediatrics and Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
authors.forename: Madhulika B
authors.initials: MB
authors.lastname: Gupta
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansson
mesh_terms: D000328:Adult; D026924:Amino Acid Transport System A / Q000378:metabolism*; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism*; D005865:Gestational Age; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D011247:Pregnancy; D046988:Proteasome Endopeptidase Complex; D021381:Protein Transport; D059748:Proteolysis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D026924:Amino Acid Transport System A; D056827:Endosomal Sorting Complexes Required for Transport; D046912:Multiprotein Complexes; C445761:SLC38A1 protein, human; C498797:SLC38A2 protein, human; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex
keywords: maternal–fetal exchange; mechanistic target of rapamycin (mTOR); pregnancy