Perspectivas atuais sobre a O-GlcNAc Transferase (OGT) na resposta ao estresse gestacional
DOI:
https://doi.org/10.11606/issn.1679-9836.v104i6e-234285Palavras-chave:
Estresse gestacional, Neurodesenvolvimento, proteína OGT, viés sexual, O-linked N-acetylglucosamine transferase, placentaResumo
A exposição ao estresse no período gestacional pode afetar o desenvolvimento fetal, desencadeando danos a curto e longo prazo, desregulando vias metabólicas e transcricionais, gerando uma resposta compensatória do organismo que pode comprometer o desenvolvimento da programação neural e fetal. A proteína O-linked N-acetylglucosamine transferase (OGT) têm sido sugerida como um potencial biomarcador de estresse pré-natal, devido sua função regulatória e seu envolvimento em diversos processos intracelulares e epigenéticos. Esta revisão narrativa da literatura reúne evidências sobre a atuação da OGT em vias metabólicas e transcricionais, e como essas vias são influenciadas pelo estresse gestacional. Permanece, no entanto, uma lacuna importante: enquanto a resposta celular ao estresse tende a aumentar a atividade da OGT, na placenta observa-se uma redução de sua expressão. Compreender esse paradoxo é essencial para esclarecer mecanismos de regulação tecido e sexo-específicos. OGT modula diversos processos celulares como transcrição, síntese e degradação de proteínas, interação ou localização proteína-proteína e resposta ao estresse. Diante situações estressoras, ocorre um aumento na atividade metabólica de OGT, como um mecanismo de resposta. No tecido placentário, o estresse gestacional pode diminuir os níveis de expressão da OGT, alterando a programação fetal, funções hipotalâmicas e fatores epigenéticos. O perfil de modificação pós-traducional da proteína OGT em vias transcricionais e epigenéticas pode ser mais favorável em placentas femininas, sendo expressa duas vezes em comparação às placentas masculinas.
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Referências
Hart B, Morgan E, Alejandro EU. Nutrient sensor signaling pathways and cellular stress in fetal growth restriction. J Mol Endocrinol. 2019;62(2):R155-R165. Doi: 10.1530/JME-18-0059
Bale TL. The placenta and neurodevelopment: sex differences in prenatal vulnerability. Dialog Clin Neurosc. 2016;18(4):459-464. Doi: 10.31887/DCNS.2016.18.4/tbale
Howerton CL, Morgan CP, Fischer DB, Bale TL. O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development. Proc Natl Acad Sci U S A. 2013;110(13):5169-74. Doi: 10.1073/pnas.1300065110
Lu S, Wei F, Li G. The evolution of the concept of stress and the framework of the stress system. Cell Stress. 2021;5(6):76-85. Doi: 10.15698/cst2021.06.250
Zachara NE, Akimoto Y, Boyce M, Hart GW. The O-GlcNAc Modification. In: Varki A, Cummings RD, Esko JD, et al., eds. Essentials of Glycobiology. 4th ed. Cold Spring Harbor Laboratory Press; 2022. Accessed October 27, 2024. http://www.ncbi.nlm.nih.gov/books/NBK579950/
Ranuncolo SM, Ghosh S, Hanover JA, Hart GW, Lewis BA. Evidence of the involvement of O-GlcNAc-modified human RNA polymerase II CTD in transcription in vitro and in vivo. J Biol Chem. 2012;287(28):23549-23561. Doi: 10.1074/jbc.M111.330910
Deplus R, Delatte B, Schwinn MK, Defrance M, Méndez J, Murphy N, et al. TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. Embo J. 2013;32(5):645-55. Doi: 10.1038/emboj.2012.357
Chu CS, Lo PW, Yeh YH, Hsu PH, Peng SH, Teng YC, et al. O-GlcNAcylation regulates EZH2 protein stability and function. Proc Natl Acad Sci U S A. 2014;111(4):1355-60. Doi: 10.1073/pnas.1323226111.
Howerton CL, Bale TL. Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction. Proc Natl Acad Sci U S A. 2014;111(26):9639-44. Doi:10.1073/pnas.1401203111
Nugent BM, O’Donnell CM, Epperson CN, Bale TL. Placental H3K27me3 establishes female resilience to prenatal insults. Nat Commun. 2018;9(1):2555. Doi: 10.1038/s41467-018-04992-1
Very N, Steenackers A, Dubuquoy C, Vermuse J, Dubuquoy L, Lefebvre T, et al. Cross regulation between mTOR signaling and O-GlcNAcylation. J Bioenerg Biomembr. 2018;50(3):213-222. Doi: 10.1007/s10863-018-9747-y
Chatham JC, Zhang J, Wende AR. Role of O-linked-acetylglucosamine protein modification in cellular (patho)physiology. Physiolog Reviews. 2021;101(2):427-93. Doi: 10.1152/physrev.00043.2019
Camilo C, Vieira LM, Torrezan AC, Sousa AB, Gouveia G, Euclydes V, et al. Identification of O-linked N-acetylglucosamine transferase (OGT) expression in human placentas as a potential biomarker of prenatal stress exposure. Europ Neuropsychopharmacol. 2022;63:e127-e128. Doi: 10.1016/j.euroneuro.2022.07.238
Zhang N, Jiang H, Zhang K, Zhu J, Wang Z, Long Y, et al. OGT as potential novel target: Structure, function and inhibitors. Chem Biol Interact. 2022;357:109886. Doi: 10.1016/j.cbi.2022.109886.
Konzman D, Abramowitz LK, Steenackers A, Mukherjee MM, Na HJ, Hanover JA. O-GlcNAc: Regulator of Signaling and Epigenetics Linked to X-linked Intellectual Disability. Front Genet. 2020;11:605263. Doi: 10.3389/fgene.2020.605263
Vaidyanathan K, Wells L. Multiple tissue-specific roles for the O-GlcNAc post-translational modification in the induction of and complications arising from type II diabetes. J Biol Chem. 2014;289(50):34466-71. Doi: 10.1074/jbc.R114.591560
Vella P, Scelfo A, Jammula S, Chiacchiera F, Williams K, Cuomo A, et al. Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol Cell. 2013;49(4):645-56. Doi: 10.1016/j.molcel.2012.12.019.
Lairson LL, Henrissat B, Davies GJ, Withers SG. Glycosyltransferases: structures, functions, and mechanisms. Annu Rev Biochem. 2008;77:521-55. Doi: 10.1146/annurev.biochem.76.061005.092322
Lazarus MB, Nam Y, Jiang J, Sliz P, Walker S. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature. 2011;469(7331):564-7. Doi: 10.1038/nature09638
Lubas WA, Hanover JA. Functional expression of O-linked GlcNAc transferase. Domain structure and substrate specificity. J Biol Chem. 2000;275(15):10983-8. Doi: 10.1074/jbc.275.15.10983
Janetzko J, Walker S. The making of a sweet modification: structure and function of O-GlcNAc transferase. J Biol Chem. 2014;289(50):34424-32. Doi: 10.1074/jbc.R114.604405
Li Y, Xie M, Men L, Du J. O-GlcNAcylation in immunity and inflammation: An intricate system (Review). Int J Mol Med. 2019;44(2):363-374. Doi: 10.3892/ijmm.2019.4238
Ruan HB, Singh JP, Li MD, Wu J, Yang X. Cracking the O-GlcNAc code in metabolism. Trends Endocrinol Metab. 2013;24(6):301-9. Doi: 10.1016/j.tem.2013.02.002
Yang X, Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol. 2017;18(7):452-65. Doi: 10.1038/nrm.2017.22
Schjoldager KT, Narimatsu Y, Joshi HJ, Clausen H. Global view of human protein glycosylation pathways and functions. Nat Rev Mol Cell Biol. 2020;21(12):729-49. Doi: 10.1038/s41580-020-00294-x
Teo CF, Wollaston-Hayden EE, Wells L. Hexosamine flux, the O-GlcNAc modification, and the development of insulin resistance in adipocytes. Mol Cell Endocrinol. 2010;318(1-2):44-53. Doi: 10.1016/j.mce.2009.09.022
Bullen JW, Balsbaugh JL, Chanda D, Shabanowitz J, Hunt DF, Neumann D, et al. Cross-talk between two essential nutrient-sensitive enzymes: O-GlcNAc transferase (OGT) and AMP-activated protein kinase (AMPK). J Biol Chem. 2014;289(15):10592-606. Doi: 10.1074/jbc.M113.523068.
Kelly AC, Kramer A, Rosario FJ, Powell TL, Jansson T. Inhibition of mechanistic target of rapamycin signaling decreases levels of O-GlcNAc transferase and increases serotonin release in the human placenta. Clin Sci (Lond). 2020;134(23):3123-36. Doi: 10.1042/CS20201050
Fisi V, Miseta A, Nagy T. The Role of Stress-Induced O-GlcNAc Protein Modification in the Regulation of Membrane Transport. Oxid Med Cell Longev. 2017;2017:1308692. Doi: 10.1155/2017/1308692
Constable S, Lim JM, Vaidyanathan K, Wells L. O-GlcNAc transferase regulates transcriptional activity of human Oct4. Glycobiology. 2017;27(10):927-37. Doi: 10.1093/glycob/cwx055
Willems AP, Gundogdu M, Kempers MJE, Giltay JC, Pfundt R, Elferink M, et al. Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients with X-linked intellectual disability. J Biol Chem. 2017;292(30):12621-31. Doi: 10.1074/jbc.M117.790097
Liu C, Li J. O-GlcNAc: A Sweetheart of the Cell Cycle and DNA Damage Response. Front Endocrinol (Lausanne). 2018;9:415. Doi: 10.3389/fendo.2018.00415
Lewis BA, Burlingame AL, Myers SA. Human RNA Polymerase II Promoter Recruitment in Vitro Is Regulated by O-Linked N-Acetylglucosaminyltransferase (OGT). J Biol Chem. 2016;291(27):14056-61. Doi: 10.1074/jbc.M115.684365
Dehennaut V, Leprince D, Lefebvre T. O-GlcNAcylation, an Epigenetic Mark. Focus on the Histone Code, TET Family Proteins, and Polycomb Group Proteins. Front Endocrinol (Lausanne). 2014;5:155. Doi: 10.3389/fendo.2014.00155
Decourcelle A, Leprince D, Dehennaut V. Regulation of Polycomb Repression by O-GlcNAcylation: Linking Nutrition to Epigenetic Reprogramming in Embryonic Development and Cancer. Front Endocrinol (Lausanne). 2019;10:117. Doi: 10.3389/fendo.2019.00117
Love DC, Krause MW, Hanover JA. O-GlcNAc cycling: emerging roles in development and epigenetics. Semin Cell Dev Biol. 2010;21(6):646-54. Doi: 10.1016/j.semcdb.2010.05.001
Nugent BM, Bale TL. The omniscient placenta: Metabolic and epigenetic regulation of fetal programming. Front Neuroendocrinol. 2015;39:28-37. Doi: 10.1016/j.yfrne.2015.09.001
Martinez MR, Dias TB, Natov PS, Zachara NE. Stress-induced O-GlcNAcylation: an adaptive process of injured cells. Biochem Soc Trans. 2017;45(1):237-49. Doi: 10.1042/BST20160153
Yaribeygi H, Panahi Y, Sahraei H, Johnston TP, Sahebkar A. The impact of stress on body function: A review. EXCLI J. 2017;16:1057-72. Doi: 10.17179/excli2017-480
Zuliani I, Lanzillotta C, Tramutola A, Francioso A, Pagnotta S, Barone E, et al. The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome. Neurotherapeutics. 2021;18(1):340-63. Doi: 10.1007/s13311-020-00978-4
Groves JA, Lee A, Yildirir G, Zachara NE. Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis. Cell Stress Chaperones. 2013;18(5):535-58. Doi:10.1007/s12192-013-0426-y
Akan I, Olivier‐Van Stichelen S, Bond MR, Hanover JA. Nutrient‐driven O‐GlcNAc in proteostasis and neurodegeneration. J Neurochem. 2018;144(1):7-34. Doi:10.1111/jnc.14242
Maltepe E, Bakardjiev AI, Fisher SJ. The placenta: transcriptional, epigenetic, and physiological integration during development. J Clin Invest. 2010;120(4):1016-25. Doi: 10.1172/JCI41211
Soma-Pillay P, Nelson-Piercy C, Tolppanen H, Mebazaa A. Physiological changes in pregnancy. Cardiovasc J Afr. 2016;27(2):89-94. Doi: 10.5830/CVJA-2016-021
Guardino CM, Schetter CD. Coping during pregnancy: a systematic review and recommendations. Health Psychol Rev. 2014;8(1):70-94. Doi: 10.1080/17437199.2012.752659
Glover V, O’Donnell KJ, O’Connor TG, Fisher J. Prenatal maternal stress, fetal programming, and mechanisms underlying later psychopathology-A global perspective. Dev Psychopathol. 2018;30(3):843-54. Doi: 10.1017/S095457941800038X
Lautarescu A, Craig MC, Glover V. Prenatal stress: Effects on fetal and child brain development. Int Rev Neurobiol. 2020;150:17-40. Doi: 10.1016/bs.irn.2019.11.002
Ning J, Yang H. O-GlcNAcylation in Hyperglycemic Pregnancies: Impact on Placental Function. Front Endocrinol (Lausanne). 2021;12:659733. Doi: 10.3389/fendo.2021.659733
Armitage JA, Khan IY, Taylor PD, Nathanielsz PW, Poston L. Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? J Physiol. 2004;561(2):355-77. Doi: 10.1113/jphysiol.2004.072009
Andres LM, Blong IW, Evans AC, Rumachik NG, Yamaguchi T, Pham ND, et al. Chemical Modulation of Protein O-GlcNAcylation via OGT Inhibition Promotes Human Neural Cell Differentiation. ACS Chem Biol. 2017;12(8):2030-9. Doi: 10.1021/acschembio.7b00232
Patrat C, Ouimette JF, Rougeulle C. X chromosome inactivation in human development. Development. 2020;147(1):dev183095. Doi: 10.1242/dev.183095
Christians JK. The Placenta’s Role in Sexually Dimorphic Fetal Growth Strategies. Reprod Sci. 2022;29(6):1895-1907. Doi: 10.1007/s43032-021-00780-3
Gabory A, Roseboom TJ, Moore T, Moore LG, Junien C. Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics. Biol Sex Differ. 2013;4(1):5. Doi: 10.1186/2042-6410-4-5
Gong S, Sovio U, Aye IL, Gaccioli F, Dopierala J, Johnson MD, et al. Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia. JCI Insight. 2018;3(13):e120723. Doi: 10.1172/jci.insight.120723
Morgan E, Chung G, Jo S, Clifton B, Wernimont SA, Alejandro EU. Gene and Protein Expression of Placental Nutrient-Stress Sensor Proteins in Fetal Growth Restriction. Stresses. 2024;4(2):308-19. Doi:10.3390/stresses4020019
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