Changes in placental amino acid transfer directly contribute to altered fetal growth, which increases the risk for perinatal complications and predisposes for the development of obesity, diabetes and cardiovascular disease later in life. Placental amino acid transfer is critically dependent on the expression of specific transporters in the plasma membrane of the trophoblast, the transporting epithelium of the human placenta. However, the molecular mechanisms regulating this process are largely unknown. Nedd4-2 is an ubiquitin ligase that catalyses the ubiquitination of proteins, resulting in proteasomal degradation. We hypothesized that inhibition of mechanistic target of rapamycin complex 1 (mTORC1) decreases amino acid uptake in primary human trophoblast (PHT) cells by activation of Nedd4-2, which increases transporter ubiquitination resulting in decreased transporter expression in the plasma membrane. mTORC 1 inhibition increased the expression of Nedd4-2, promoted ubiquitination and decreased the plasma membrane expression of SNAT2 (an isoform of the System A amino acid transporter) and LAT1 (a System L amino acid transporter isoform), resulting in decreased cellular amino acid uptake. Nedd4-2 silencing markedly increased the trafficking of SNAT2 and LAT1 to the plasma membrane, which stimulated cellular amino acid uptake. mTORC1 inhibition by silencing of raptor failed to decrease amino acid transport following Nedd4-2 silencing. In conclusion, we have identified a novel link between mTORC1 signalling and ubiquitination, a common posttranslational modification. Because placental mTORC1 is inhibited in fetal growth restriction and activated in fetal overgrowth, we propose that regulation of placental amino acid transporter ubiquitination by mTORC1 and Nedd4-2 constitutes a molecular mechanisms underlying abnormal fetal growth.
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Radiation nephropathy is mitigated by EET-A and also by captopril. The severe histological injury of radiation nephropathy includes cast formation and mesangiolysis. Both are significantly attenuated by EET-A or captopril. PAS stained kidney, 200x magnification. For further details see pp. 587–599. Image kindly provided by Dr. Md Abdul Hye Khan.
Research Article|
February 17 2016
Regulation of amino acid transporter trafficking by mTORC1 in primary human trophoblast cells is mediated by the ubiquitin ligase Nedd4-2
Fredrick J. Rosario;
*Division of Reproductive Sciences, Department of OB/GYN, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, U.S.A.
Correspondence: Fredrick J. Rosario (email [email protected]).
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Kris Genelyn Dimasuay;
Kris Genelyn Dimasuay
†Department of Medicine, Peter Doherty Institute, The University of Melbourne, Carlton, Victoria 3010, Australia
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Yoshikatsu Kanai;
Yoshikatsu Kanai
‡Division of Bio-System Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
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Theresa L. Powell;
Theresa L. Powell
§Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, U.S.A.
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Thomas Jansson
Thomas Jansson
*Division of Reproductive Sciences, Department of OB/GYN, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, U.S.A.
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Publisher: Portland Press Ltd
Received:
August 11 2015
Revision Received:
November 10 2015
Accepted:
November 25 2015
Accepted Manuscript online:
November 25 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 Authors; published by Portland Press Limited
2016
Clin Sci (Lond) (2016) 130 (7): 499–512.
Article history
Received:
August 11 2015
Revision Received:
November 10 2015
Accepted:
November 25 2015
Accepted Manuscript online:
November 25 2015
Citation
Fredrick J. Rosario, Kris Genelyn Dimasuay, Yoshikatsu Kanai, Theresa L. Powell, Thomas Jansson; Regulation of amino acid transporter trafficking by mTORC1 in primary human trophoblast cells is mediated by the ubiquitin ligase Nedd4-2. Clin Sci (Lond) 1 April 2016; 130 (7): 499–512. doi: https://doi.org/10.1042/CS20150554
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