Posttranslational modifications and its role in habitual miscarriage: prognosis, diagnosis and new approaches to therapy
https://doi.org/10.29413/ABS.2025-10.5.4
Abstract
The prevalence of recurrent pregnancy loss (RPL) in women ranges from 1 to 5 %. Among the known causes of RPL, the role of post-translational protein modifications (PTMP) has been studied in recent years. These are protein structure transformations that complete the formation of their molecule or participate in the regulation of the functions of this molecule, catalyzed by specific enzymes.
The aim. To assess the role of PTMP in the pathogenesis of RPL, as well as to determine potential biomarkers and therapeutic targets of RPL.
Material. A search of publications by keywords was conducted in the electronic databases PubMed/MEDLINE and Google Scholar, published before December 2024.
Results. PTMB plays an important role in the processes of trophoblast invasion, endometrial decidualization and embryo implantation, which makes them significant for understanding reproductive dysfunction. The use of mass spectrometry to study PTMB opens up new possibilities for the diagnosis and prognosis of RPL. Epigenetic therapy of RPL demonstrates efficacy and a lower probability of side effects compared to traditional methods. Despite significant prospects, research in this area is accompanied by difficulties associated with heterogeneity of terminology and ethical issues.
Conclusion. PTMB in the context of RPL can contribute to the improvement of diagnostic and therapeutic strategies in reproductive medicine. Further development of methodologies for studying PTMB is needed.
About the Authors
A. M. Ziganshin
Bashkir State Medical University
Russian Federation
Russian Federation
Aydar M. Ziganshin – Dr. Sc. (Med.), Professor of the Department of Obstetrics and Gynecology with a course at the Institute of Additional Professional Education
3 Lenin St., 450008 Ufa, Russian Federation
G. B. Dikke
F.I. Inozemtsev Academy of Medical Education
Russian Federation
Russian Federation
Galina B. Dikke –Dr. Sc. (Med.), Professor, Department of Obstetrics and Gynecology with a Course of Reproductive Medicine
22 Moskovsky Ave., St. Petersburg 190013, Russian Federation
A. M. Musina
Bashkir State Medical University
Russian Federation
Russian Federation
Aliya M. Musina – 5th year student of the Faculty of Medicine
3 Lenin St., 450008 Ufa, Russian Federation
R. R. Bayanova
Bashkir State Medical University
Russian Federation
Russian Federation
Regina R. Bayanova – 5th year student of the Faculty of Medicine
3 Lenin St., 450008 Ufa, Russian Federation
A. L. Frolov
Republican Clinical University of the Ministry of Health of the Republic of Belarus, Perinatal Center
Russian Federation
Russian Federation
Alexey L. Frolov – Cand. Sc. (Med.), Honored Doctor of the Republic of Bashkortostan, distinguished physician of the Russian Federation and the Republic of Bashkortostan, Head of the Operating Unit. No. 2
Batyrskaya str., 31, Ufa 450106, Russian Federation
References
1. Rasmark Roepke E, Matthiesen L, Rylance R, Christiansen OB. Is the incidence of recurrent pregnancy loss increasing? A retrospective register-based study in Sweden. Acta Obstet Gynecol Scand. 2017; 96(11): 1365-1372. doi: 10.1111/aogs.13210
2. Tetruashvili NK. Habitual miscarriage. Obstetrics and Gynecology: News. Opinions. Training. 2017; 4(18): 70-87. (In Russ.). doi: 10.24411/2303-9698-2017-00010
3. Dimitriadis E, Menkhorst E, Saito S, et al. Recurrent pregnancy loss. Nat Rev Dis Primers. 2020; 6(1): 98. doi: 10.1038/s41572-020-00228-z
4. Malyshkina AI, Nazarova AO, Batrak NV, et al. Sociomedical characteristics of patients with recurrent miscarriage. Russian Bulletin of Obstetrician-Gynecologist. 2014; 14(6): 4348. (In Russ.).
5. Pogorelova TN, Gun’ko VO, Nikashina AA, Alliluev IA, Botasheva TL. Post-translational modifications and differential expression of proteins in placental insufficiency. Russian Journal of Human Reproduction. 2016; 22(6): 115119. (In Russ.). doi: 10.17116/repro2016226115-119
6. Pieroni L, Iavarone F, Olianas A, et al. Enrichments of post-translational modifications in proteomic studies. J Sep Sci. 2020; 43(1): 313-336. doi: 10.1002/jssc.201900804
7. Pan S, Chen R. Pathological implication of protein post-translational modifications in cancer. Mol Aspects Med. 2022; 86: 101097. doi: 10.1016/j.mam.2022.101097
8. Tur-Torres MH, Garrido-Gimenez C, Alijotas-Reig J. Genetics of recurrent miscarriage and fetal loss. Best Pract Res Clin Obstet Gynaecol. 2017; 42: 11-25. doi: 10.1016/j.bpobgyn.2017.03.007
9. Eichler J. Protein glycosylation. Curr Biol. 2019; 29(7): R229-R231. doi: 10.1016/j.cub.2019.01.003
10. de Lima Castro M, Dos Passos RR Jr, Justina VD, et al. Physiological and pathological evidence of O-GlcNAcylation regulation during pregnancy related process. Placenta. 2023; 141: 43-50. doi: 10.1016/j.placenta.2023.04.018
11. Keembiyehetty C, Love DC, Harwood KR, et al. Conditional knock-out reveals a requirement for O-linked N-Acetylglucosaminase (O-GlcNAcase) in metabolic homeostasis. J Biol Chem. 2015; 290(11): 7097-113. doi: 10.1074/jbc.M114.617779
12. Pestrikova TYu, Iurasova EA, Tkachenko VA. Placental insufficiency as the underlying condition of the complications and outcomes of the gestation period. Russian Bulletin of Obstetrician-Gynecologist. 2020; 20(1): 515. (In Russ.). doi: 10.17116/rosakush2020200115
13. Yang YR, Jang HJ, Lee YH, et al. O-GlcNAc cycling enzymes control vascular development of the placenta by modulating the levels of HIF-1α. Placenta. 2015; 36(10): 1063-8. doi: 10.1016/j.placenta.2015.08.001
14. Ruane PT, Tan CMJ, Adlam DJ, et al. Protein O-GlcNAcylation promotes trophoblast differentiation at implantation. Cells. 2020; 9(10): 2246. doi: 10.3390/cells9102246
15. Liu J, Shao X, Qin W, et al. Quantitative chemoproteomics reveals O-GlcNAcylation of cystathionine γ-lyase (CSE) represses trophoblast syncytialization. Cell Chem Biol. 2021; 28(6): 788-801.e5. doi: 10.1016/j.chembiol.2021.01.024
16. Lima VV, Dela Justina V, Dos Passos RR Jr, et al. O-GlcNAc modification during pregnancy: focus on placental environment. Front Physiol. 2018; 9: 1263. doi: 10.3389/fphys.2018.01263
17. Lai Y, Fu Z, Gao Y, Ma N, Li L. Hypoxia-inducible factors (HIFs) in early pregnancy: implications for miscarriage†. Biol Reprod. 2024; 111(5): 987-999. doi: 10.1093/biolre/ioae139
18. Shi L, Kang K, Wang Z, et al. Glucose Regulates Glucose Transport and Metabolism via mTOR Signaling Pathway in Bovine Placental Trophoblast Cells. Animals (Basel). 2023; 14(1): 40. doi: 10.3390/ani14010040
19. Watkins AJ, Lucas ES, Marfy-Smith S, et al. Maternal nutrition modifies trophoblast giant cell phenotype and fetal growth in mice. Reproduction. 2015; 149(6): 563-75. doi: 10.1530/REP-14-0667
20. Han X, Li X, Liu H, et al. OGlcNAc modification influences endometrial receptivity by promoting endometrial cell proliferation, migration and invasion. Oncol Rep. 2019; 42(5): 2065-2074. doi: 10.3892/or.2019.7317
21. Wang AJ, Wang A, Hascall V. Detoxification of Hyperglycemia-induced Glucose Toxicity by the Hexosamine Biosynthetic Pathway. Front Biosci (Landmark Ed). 2024; 29(2): 71. doi: 10.31083/j.fbl2902071
22. Yu M, Qin H, Wang H, et al. N-glycosylation of uterine endometrium determines its receptivity. J Cell Physiol. 2020; 235(2): 1076-1089. doi: 10.1002/jcp.29022
23. Mortimer NT, Fischer ML, Waring AL, et al. Extracellular matrix protein N-glycosylation mediates immune self-tolerance in Drosophila melanogaster. Proc Natl Acad Sci USA. 2021; 118(39): e2017460118. doi: 10.1073/pnas.2017460118
24. Ferrer A, Starosta RT, Ranatunga W, et al. Fetal glycosylation defect due to ALG3 and COG5 variants detected via amniocentesis: complex glycosylation defect with embryonic lethal phenotype. Mol Genet Metab. 2020; 131(4): 424-429. doi: 10.1016/j.ymgme.2020.11.003
25. Liu C, Liang X, Wang J, et al. Protein O-fucosyltransferase 1 promotes trophoblast cell proliferation through activation of MAPK and PI3K/Akt signaling pathways. Biomed Pharmacother. 2017; 88: 95-101. doi: 10.1016/j.biopha.2017.01.026
26. Yang Y, Zhang D, Qin H, Liu S, Yan Q. poFUT1 promotes endometrial decidualization by enhancing the O-fucosylation of Notch1. EBioMedicine. 2019; 44: 563-573. doi: 10.1016/j.ebiom.2019.05.027
27. Zheng Q, Zhang D, Yang Yu, et al. MicroRNA-200c impairs uterine receptivity formation by targeting FUT4 and α1,3-fucosylation. Cell Death Differ. 2017; 24(12): 2161-2172. doi: 10.1038/cdd.2017.136
28. Dosiou C, Giudice LC. Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives. Endocr Rev. 2005; 26(1): 44-62. doi: 10.1210/er.2003-0021
29. Yang L, Zhang X, Gu Y, et al. SEC5 is involved in M2 polarization of macrophages via the STAT6 pathway, and its dysfunction in decidual macrophages is associated with recurrent spontaneous abortion. Front Cell Dev Biol. 2022; 10: 891748. doi: 10.3389/fcell.2022.891748
30. Li A, Li S, Zhang C, et al. FPR2 serves a role in recurrent spontaneous abortion by regulating trophoblast function via the PI3K/AKT signaling pathway. Mol Med Rep. 2021; 24(6): 838. doi: 10.3892/mmr.2021.12478
31. Gao L, Xu QH, Ma LN, et al. Trophoblast-derived Lactic Acid Orchestrates Decidual Macrophage Differentiation via SRC/LDHA Signaling in Early Pregnancy. Int J Biol Sci. 2022; 18(2): 599-616. doi: 10.7150/ijbs.6781690/cells12050711
32. Cai X, Jiang Y, Cao Z, et al. Mst1-mediated phosphorylation of Nur77 improves the endometrial receptivity in human and mice. EBioMedicine. 2023; 88: 104433. doi: 10.1016/j.ebiom.2022.104433
33. Liu B, Wu H, Huang Q, et al. Phosphorylated STAT3 inhibited the proliferation and suppression of decidual Treg cells in unexplained recurrent spontaneous abortion. Int Immunopharmacol. 2020; 82: 106337. doi: 10.1016/j.intimp.2020.106337
34. Liu X, Zhao J, Luan X, et al. SPARCL1 impedes trophoblast migration and invasion by down-regulating ERK phosphorylation and AP-1 production and altering EMT-related molecule expression. Placenta. 2020; 89: 33-41. doi: 10.1016/j.placenta.2019.10.007
35. Chang HM, Yeh ETH. SUMO: From Bench to Bedside. Physiol Rev. 2020; 100(4): 1599-1619. doi: 10.1152/physrev.00025.2019
36. Jones KT. Anaphase-promoting complex control in female mouse meiosis. Results Probl Cell Differ. 2011; 53: 343-63. doi: 10.1007/978-3-642-19065-0_15
37. Yamaguchi T, Sharma P, Athanasiou M, et al. Mutation of SENP1/SuPr-2 reveals an essential role for desumoylation in mouse development. Mol Cell Biol. 2005; 25(12): 5171-82. doi: 10.1128/MCB.25.12.5171-5182.2005
38. Yu HI, Hsu T, Maruyama EO, et al. The requirement of SUMO2/3 for SENP2 mediated extraembryonic and embryonic development. Dev Dyn. 2020; 249(2): 237-244. doi: 10.1002/dvdy.125
39. Huang CJ, Wu D, Jiao XF, et al. Maternal SENP7 programs meiosis architecture and embryo survival in mouse. Biochim Biophys Acta Mol Cell Res. 2017; 1864(7): 1195-1206. doi: 10.1016/j.bbamcr.2017.03.005
40. Snider NT, Omary MB. Post-translational modifications of intermediate filament proteins: mechanisms and functions. Nat Rev Mol Cell Biol. 2014; 15(3): 163-77. doi: 10.1038/nrm3753
41. Hayashi T, Seki M, Maeda D, et al. Ubc9 is essential for viability of higher eukaryotic cells. Exp Cell Res. 2002; 280(2): 212-21. doi: 10.1006/excr.2002.5634
42. Nacerddine K, Lehembre F, Bhaumik M, et al. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev Cell. 2005; 9(6): 769-79. doi: 10.1016/j.devcel.2005.10.007
43. Feitosa WB, Hwang K, Morris PL. Temporal and SUMO-specific SUMOylation contribute to the dynamics of Polo-like kinase 1 (PLK1) and spindle integrity during mouse oocyte meiosis. Developmental biology. 2018. 434(2): 278-291. doi: 10.1016/j.ydbio.2017.12.011
44. Wang J, Zhou Q, Ding J, et al. The conceivable functions of protein ubiquitination and deubiquitination in reproduction. Front Physiol. 2022; 13: 886261. doi: 10.3389/fphys.2022.886261
45. Ding J, Cheng Y, Zhang Y, et al. The miR-27a-3p/USP25 axis participates in the pathogenesis of recurrent miscarriage by inhibiting trophoblast migration and invasion. J Cell Physiol. 2019; 234(11): 19951-19963. doi: 10.1002/jcp.28593
46. Wang J, Ding J, Zhang S, et al. Decreased USP2a expression inhibits trophoblast invasion and associates with recurrent miscarriage. Front Immunol. 2021; 12: 717370. doi: 10.3389/fimmu.2021.717370
47. Fraile JM, Campos-Iglesias D, Rodríguez F, et al. Loss of the deubiquitinase USP36 destabilizes the RNA helicase DHX33 and causes preimplantation lethality in mice. J Biol Chem. 2018; 293(6): 2183-2194. doi: 10.1074/jbc.M117.788430
48. Feng J, Yin H, Baturuhu Dai Y, et al. Research progress of E3 ubiquitin ligase regulating biological behavior of human placental trophoblast cells. Front Endocrinol (Lausanne). 2023; 14: 1124041. doi: 10.3389/fendo.2023.1124041
49. Wu L, Liu Q, Fan C, et al. MALAT1 recruited the E3 ubiquitin ligase FBXW7 to induce CRY2 ubiquitin-mediated degradation and participated in trophoblast migration and invasion. J Cell Physiol. 2021; 236(3): 2169-2177. doi: 10.1002/jcp.30003
50. Chen LJ, Zhang NN, Zhou CX, et al. Gm364 coordinates MIB2/DLL3/Notch2 to regulate female fertility through AKT activation. Cell Death Differ. 2022; 29(2): 366-380. doi: 10.1038/s41418-021-00861-5
51. Xia P, Wang S, Du Y, et al. WASH inhibits autophagy through suppression of Beclin 1 ubiquitination. EMBO J. 2013; 32(20): 2685-96. doi: 10.1038/emboj.2013.189
52. Xie J, Liang T, Zhao J, et al. Lnc-HZ08 regulates BPDE-induced trophoblast cell dysfunctions by promoting PI3K ubiquitin degradation and is associated with miscarriage. Cell Biol Toxicol. 2022; 38(2): 291-310. doi: 10.1007/s10565-021-09606-z
53. Heger K, Wickliffe KE, Ndoja A, et al. OTULIN limits cell death and inflammation by deubiquitinating LUBAC. Nature. 2018; 559(7712): 120-124. doi: 10.1038/s41586-018-0256-2
54. Wei H, Mundade R, Lange KC, Lu T. Protein arginine methylation of non-histone proteins and its role in diseases. Cell Cycle. 2014; 13(1): 32-41. doi: 10.4161/cc.27353
55. Swiercz R, Cheng D, Kim D, Bedford MT. Ribosomal protein rpS2 is hypomethylated in PRMT3-deficient mice. J Biol Chem. 2007; 282(23): 16917-23. doi: 10.1074/jbc.M609778200
56. Hao F, Tang LC, Sun JX, et al. Decreased nitric oxide content mediated by asymmetrical dimethylarginine and protein l-arginine methyltransferase 3 in macrophages induces trophoblast apoptosis: a potential cause of recurrent miscarriage. Human Reproduction. 2021; 36(12): 3049-3061. doi: 10.1093/humrep/deab225
57. Bergo MO, Leung GK, Ambroziak P, et al. Isoprenylcysteine carboxyl methyltransferase deficiency in mice. J Biol Chem. 2001; 276(8): 5841-5. doi: 10.1074/jbc.C000831200
58. Xu R, Li C, Liu X, Gao S. Insights into epigenetic patterns in mammalian early embryos. Protein Cell. 2021; 12(1): 7-28. doi: 10.1007/s13238-020-00757-z
59. Matoba S, Liu Y, Lu F, et al. Embryonic development following somatic cell nuclear transfer impeded by persisting histone methylation. Cell. 2014; 159(4): 884-95. doi: 10.1016/j.cell.2014.09.055
60. Fatima N, Ahmed SH, Salhan S, Rehman SM, Kaur J, Owais M, Chauhan SS. Study of methyl transferase (G9aMT) and methylated histone (H3-K9) expressions in unexplained recurrent spontaneous abortion (URSA) and normal early pregnancy. Mol Hum Reprod. 2011; 17(11): 693-701. doi: 10.1093/molehr/gar038
61. Zhou Q, Xiong Y, Qu B, et al. DNA Methylation and Recurrent Pregnancy Loss: A Mysterious Compass? Front Immunol. 2021; 12: 738962. doi: 10.3389/fimmu.2021.738962
62. Inoue A, Jiang L, Lu F, Suzuki T, Zhang Y. Maternal H3K27me3 controls DNA methylation-independent imprinting. Nature. 2017; 547(7664): 419-424. doi: 10.1038/nature23262
63. Wen X, Zhang Q, Zhou L, et al. Intrachromosomal Looping and Histone K27 Methylation Coordinately Regulates the lncRNA H19-Fetal Mitogen IGF2 Imprinting
64. Cluster in the Decidual Microenvironment of Early Pregnancy. Cells. 2022; 11(19): 3130. doi: 10.3390/cells11193130
65. Fatima N, Ahmed SH, Chauhan SS, et al. Structural equation modelling analysis determining causal role among methyltransferases, methylation, and apoptosis during human pregnancy and abortion. Scientific Reports. 2020; 10(1): 12408. doi: 10.1038/s41598-020-68270-1
66. Sakai N, Maruyama T, Sakurai R, et al. Involvement of histone acetylation in ovarian steroid-induced decidualization of human endometrial stromal cells. J Biol Chem. 2003; 278(19): 16675-82. doi: 10.1074/jbc.M211715200
67. Chen X, Song QL, Li ZH, et al. Deletion of ACLY Disrupts Histone Acetylation and IL-10 Secretion in Trophoblasts, Which Inhibits M2 Polarization of Macrophages: A Possible Role in Recurrent Spontaneous Abortion. Oxid Med Cell Longev. 2022; 2022: 5216786. doi: 10.1155/2022/5216786
68. Wang P, Zhao C, Zhou H, et al. Dysregulation of Histone Deacetylases Inhibits Trophoblast Growth during Early Placental Development Partially through TFEB-Dependent Autophagy-Lysosomal Pathway. Int J Mol Sci. 2023; 24(15): 11899. doi: 10.3390/ijms241511899
69. Zhao P, Wang H, Wang H, et al. Essential roles of HDAC1 and 2 in lineage development and genome-wide DNA methylation during mouse preimplantation development. Epigenetics. 2020; 15(4): 369-385. doi: 10.1080/15592294.2019.1669375
70. Bhaskara S, Chyla BJ, Amann JM, et al. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell. 2008; 30(1): 61-72. doi: 10.1016/j.molcel.2008.02.030
71. Kim TH, Yoo JY, Choi KC, et al. Loss of HDAC3 results in nonreceptive endometrium and female infertility. Sci Transl Med. 2019; 11(474): eaaf7533. doi: 10.1126/scitranslmed. aaf7533
72. Narita T, Weinert BT, Choudhary C. Functions and mechanisms of non-histone protein acetylation. Nat Rev Mol Cell Biol. 2019; 20(3): 156-174. doi: 10.1038/s41580-018-0081-3
73. Lee AR, Thanh Ha L, Kishigami S, Hosoi Y. Abnormal lysine acetylation with postovulatory oocyte aging. Reprod Med Biol. 2013; 13(2): 81-86. doi: 10.1007/s12522-013-0172-y
74. Kalebic N, Sorrentino S, Perlas E, et al. αTAT1 is the major α-tubulin acetyltransferase in mice. Nat Commun. 2013; 4: 1962. doi: 10.1038/ncomms2962
75. Wiesel-Motiuk N, Assaraf YG. The key roles of the lysine acetyltransferases KAT6A and KAT6B in physiology and pathology. Drug Resist Updat. 2020; 53: 100729. doi: 10.1016/j.drup.2020.100729
76. Fukushima A, Zhang L, Huqi A, et al. Acetylation contributes to hypertrophy-caused maturational delay of cardiac energy metabolism. JCI Insight. 2018; 3(10): e99239. doi: 10.1172/jci.insight.99239
77. Dikalova AE, Pandey A, Xiao L, et al. Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress. Circ Res. 2020; 126(4): 439-452. doi: 10.1161/CIRCRESAHA.119.315767
78. Zhou B, Hao Q, Liang Y, Kong E. Protein palmitoylation in cancer: molecular functions and therapeutic potential. Mol Oncol. 2023; 17(1): 3-26. doi: 10.1002/1878-0261.13308
79. Wu L, Li J, Xu HL, et al. IL-7/IL-7R signaling pathway might play a role in recurrent pregnancy losses by increasing inflammatory Th17 cells and decreasing Treg cells. Am J Reprod Immunol. 2016; 76(6): 454-464. doi: 10.1111/aji.12588
80. Zhang M, Zhou L, Xu Y, et al. A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis. Nature. 2020; 586(7829): 434-439. doi: 10.1038/s41586-020-2799-2
81. Ding J, Yin T, Yan N, et al. FasL on decidual macrophages mediates trophoblast apoptosis: A potential cause of recurrent miscarriage. Int J Mol Med. 2019; 43(6): 2376-2386. doi: 10.3892/ijmm.2019.4146
Review
For citations:
Ziganshin A.M., Dikke G.B., Musina A.M., Bayanova R.R., Frolov A.L. Posttranslational modifications and its role in habitual miscarriage: prognosis, diagnosis and new approaches to therapy. Acta Biomedica Scientifica. 2025;10(5):38-51. (In Russ.) https://doi.org/10.29413/ABS.2025-10.5.4
Views:
71
.png)
Email this article 
