PMID- 26374858 OWN - NLM STAT- MEDLINE DCOM- 20151222 LR - 20211203 IS - 1470-8736 (Electronic) IS - 0143-5221 (Print) IS - 0143-5221 (Linking) VI - 129 IP - 12 DP - 2015 Dec TI - Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2 in human IUGR. PG - 1131-41 LID - 10.1042/CS20150511 [doi] AB - 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. CI - (c) 2015 Authors; published by Portland Press Limited. FAU - Chen, Yi-Yung AU - Chen YY AD - 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. FAU - Rosario, Fredrick J AU - Rosario FJ AD - Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A. FAU - Shehab, Majida Abu AU - Shehab MA AD - Children's Health Research Institute, University of Western Ontario, London, Ontario N6C 2V5, Canada. FAU - Powell, Theresa L AU - Powell TL AD - 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. FAU - Gupta, Madhulika B AU - Gupta MB AD - 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. FAU - Jansson, Thomas AU - Jansson T AD - Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A. LA - eng GR - R01 HD068370/HD/NICHD NIH HHS/United States GR - HD068370/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20150915 PL - England TA - Clin Sci (Lond) JT - Clinical science (London, England : 1979) JID - 7905731 RN - 0 (Amino Acid Transport System A) RN - 0 (Endosomal Sorting Complexes Required for Transport) RN - 0 (Multiprotein Complexes) RN - 0 (SLC38A1 protein, human) RN - 0 (SLC38A2 protein, human) RN - EC 2.3.2.26 (Nedd4 Ubiquitin Protein Ligases) RN - EC 2.3.2.26 (Nedd4 protein, human) RN - EC 2.3.2.26 (Nedd4L protein, human) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) SB - IM MH - Adult MH - Amino Acid Transport System A/*metabolism MH - Case-Control Studies MH - Cell Membrane/*metabolism MH - Cells, Cultured MH - Endoplasmic Reticulum Stress MH - Endosomal Sorting Complexes Required for Transport/metabolism MH - Female MH - Fetal Growth Retardation/*metabolism MH - Gestational Age MH - Humans MH - Male MH - Mechanistic Target of Rapamycin Complex 1 MH - Mechanistic Target of Rapamycin Complex 2 MH - Multiprotein Complexes/metabolism MH - Nedd4 Ubiquitin Protein Ligases MH - Pregnancy MH - Proteasome Endopeptidase Complex MH - Protein Transport MH - Proteolysis MH - Signal Transduction MH - TOR Serine-Threonine Kinases/metabolism MH - Trophoblasts/*metabolism MH - Ubiquitin-Protein Ligases/metabolism MH - Ubiquitination PMC - PMC4614027 OTO - NOTNLM OT - maternal-fetal exchange OT - mechanistic target of rapamycin (mTOR) OT - pregnancy EDAT- 2015/09/17 06:00 MHDA- 2015/12/23 06:00 PMCR- 2015/10/22 CRDT- 2015/09/17 06:00 PHST- 2015/07/21 00:00 [received] PHST- 2015/09/14 00:00 [accepted] PHST- 2015/09/17 06:00 [entrez] PHST- 2015/09/17 06:00 [pubmed] PHST- 2015/12/23 06:00 [medline] PHST- 2015/10/22 00:00 [pmc-release] AID - CS20150511 [pii] AID - 10.1042/CS20150511 [doi] PST - ppublish SO - Clin Sci (Lond). 2015 Dec;129(12):1131-41. doi: 10.1042/CS20150511. Epub 2015 Sep 15.