PMID- 37957724 OWN - NLM STAT- MEDLINE DCOM- 20231129 LR - 20231129 IS - 1478-811X (Electronic) IS - 1478-811X (Linking) VI - 21 IP - 1 DP - 2023 Nov 13 TI - CHOP upregulation and dysregulation of the mature form of the SNAT2 amino acid transporter in the placentas from small for gestational age newborns. PG - 326 LID - 10.1186/s12964-023-01352-5 [doi] LID - 326 AB - BACKGROUND: The placentas from newborns that are small for gestational age (SGA; birth weight < -2 SD for gestational age) may display multiple pathological characteristics. A key determinant of fetal growth and, therefore, birth weight is placental amino acid transport, which is under the control of the serine/threonine kinase mechanistic target of rapamycin (mTOR). The effects of endoplasmic reticulum (ER) stress on the mTOR pathway and the levels of amino acid transporters are not well established. METHODS: Placentas from SGA and appropriate for gestational age (AGA) newborns and the human placental BeWo cell line exposed to the ER stressor tunicamycin were used. RESULTS: We detected a significant increase in the levels of C/EBP homologous protein (CHOP) in the placentas from SGA newborns compared with those from AGA newborns, while the levels of other ER stress markers were barely affected. In addition, placental mTOR Complex 1 (mTORC1) activity and the levels of the mature form of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) were also reduced in the SGA group. Interestingly, CHOP has been reported to upregulate growth arrest and DNA damage-inducible protein 34 (GADD34), which in turn suppresses mTORC1 activity. The GADD34 inhibitor guanabenz attenuated the increase in CHOP protein levels and the reduction in mTORC1 activity caused by the ER stressor tunicamycin in the human placental cell line BeWo, but it did not recover mature SNAT2 protein levels, which might be reduced as a result of defective glycosylation. CONCLUSIONS: Collectively, these data reveal that GADD34A activity and glycosylation are key factors controlling mTORC1 signaling and mature SNAT2 levels in trophoblasts, respectively, and might contribute to the SGA condition. Video Abstract. CI - (c) 2023. The Author(s). FAU - Barroso, Emma AU - Barroso E AD - Unitat de Farmacologia, Facultat de Farmacia I Ciencies de L'Alimentacio, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain. AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. AD - Pediatric Research Institute-Hospital Sant Joan de Deu, Esplugues de Llobregat, Spain. FAU - Diaz, Marta AU - Diaz M AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. AD - Pediatric Research Institute-Hospital Sant Joan de Deu, Esplugues de Llobregat, Spain. AD - Endocrinology, Pediatric Research Institute, Sant Joan de Deu Children's Hospital, Barcelona, Esplugues, Spain. FAU - Reguera, Ana Cristina AU - Reguera AC AD - Unitat de Farmacologia, Facultat de Farmacia I Ciencies de L'Alimentacio, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain. AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. AD - Pediatric Research Institute-Hospital Sant Joan de Deu, Esplugues de Llobregat, Spain. FAU - Peyman, Mona AU - Peyman M AD - Unitat de Farmacologia, Facultat de Farmacia I Ciencies de L'Alimentacio, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain. AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. AD - Pediatric Research Institute-Hospital Sant Joan de Deu, Esplugues de Llobregat, Spain. FAU - Balsinde, Jesus AU - Balsinde J AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. AD - Instituto de Biologia y Genetica Molecular, Consejo Superior de Investigaciones Cientificas, Valladolid, Spain. FAU - Jurado-Aguilar, Javier AU - Jurado-Aguilar J AD - Unitat de Farmacologia, Facultat de Farmacia I Ciencies de L'Alimentacio, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain. AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. AD - Pediatric Research Institute-Hospital Sant Joan de Deu, Esplugues de Llobregat, Spain. FAU - Zhang, Meijian AU - Zhang M AD - Unitat de Farmacologia, Facultat de Farmacia I Ciencies de L'Alimentacio, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain. AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. AD - Pediatric Research Institute-Hospital Sant Joan de Deu, Esplugues de Llobregat, Spain. FAU - Rostami, Adel AU - Rostami A AD - Unitat de Farmacologia, Facultat de Farmacia I Ciencies de L'Alimentacio, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain. AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. AD - Pediatric Research Institute-Hospital Sant Joan de Deu, Esplugues de Llobregat, Spain. FAU - Palomer, Xavier AU - Palomer X AD - Unitat de Farmacologia, Facultat de Farmacia I Ciencies de L'Alimentacio, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain. AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. AD - Pediatric Research Institute-Hospital Sant Joan de Deu, Esplugues de Llobregat, Spain. FAU - Ibanez, Lourdes AU - Ibanez L AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. AD - Pediatric Research Institute-Hospital Sant Joan de Deu, Esplugues de Llobregat, Spain. AD - Endocrinology, Pediatric Research Institute, Sant Joan de Deu Children's Hospital, Barcelona, Esplugues, Spain. FAU - Vazquez-Carrera, Manuel AU - Vazquez-Carrera M AD - Unitat de Farmacologia, Facultat de Farmacia I Ciencies de L'Alimentacio, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Av. Joan XXIII 27-31, 08028, Barcelona, Spain. mvazquezcarrera@ub.edu. AD - Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. mvazquezcarrera@ub.edu. AD - Pediatric Research Institute-Hospital Sant Joan de Deu, Esplugues de Llobregat, Spain. mvazquezcarrera@ub.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Video-Audio Media DEP - 20231113 PL - England TA - Cell Commun Signal JT - Cell communication and signaling : CCS JID - 101170464 RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 11089-65-9 (Tunicamycin) RN - 0 (DDIT3 protein, human) RN - 0 (SLC38A2 protein, human) RN - 147336-12-7 (Transcription Factor CHOP) RN - 0 (Amino Acid Transport System A) SB - IM MH - Female MH - Humans MH - Infant, Newborn MH - Pregnancy MH - Birth Weight MH - Fetal Growth Retardation/genetics/metabolism MH - Gestational Age MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - *Placenta/metabolism MH - *TOR Serine-Threonine Kinases/metabolism MH - Tunicamycin/pharmacology MH - Up-Regulation MH - *Transcription Factor CHOP/genetics MH - *Amino Acid Transport System A/genetics PMC - PMC10644500 OTO - NOTNLM OT - CHOP OT - ER stress OT - GADD34 OT - Placenta OT - SNAT2 OT - mTORC1 COIS- The authors declare no competing interests. EDAT- 2023/11/14 06:43 MHDA- 2023/11/15 06:42 PMCR- 2023/11/13 CRDT- 2023/11/14 00:15 PHST- 2023/06/21 00:00 [received] PHST- 2023/10/10 00:00 [accepted] PHST- 2023/11/15 06:42 [medline] PHST- 2023/11/14 06:43 [pubmed] PHST- 2023/11/14 00:15 [entrez] PHST- 2023/11/13 00:00 [pmc-release] AID - 10.1186/s12964-023-01352-5 [pii] AID - 1352 [pii] AID - 10.1186/s12964-023-01352-5 [doi] PST - epublish SO - Cell Commun Signal. 2023 Nov 13;21(1):326. doi: 10.1186/s12964-023-01352-5.