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Kempkes","award":["15\/2021"],"award-info":[{"award-number":["15\/2021"]}]},{"DOI":"10.13039\/501100009560","name":"University Medical Center Giessen and Marburg UKGM","doi-asserted-by":"publisher","award":["Ko1855\/4-1"],"award-info":[{"award-number":["Ko1855\/4-1"]}],"id":[{"id":"10.13039\/501100009560","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009560","name":"University Medical Center Giessen and Marburg UKGM","doi-asserted-by":"publisher","award":["03\/2018"],"award-info":[{"award-number":["03\/2018"]}],"id":[{"id":"10.13039\/501100009560","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009560","name":"University Medical Center Giessen and Marburg UKGM","doi-asserted-by":"publisher","award":["15\/2021"],"award-info":[{"award-number":["15\/2021"]}],"id":[{"id":"10.13039\/501100009560","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Open Access Publication Fund of Philipps-Universit\u00e4t Marburg with support of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","award":["Ko1855\/4-1"],"award-info":[{"award-number":["Ko1855\/4-1"]}]},{"name":"Open Access Publication Fund of Philipps-Universit\u00e4t Marburg with support of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","award":["03\/2018"],"award-info":[{"award-number":["03\/2018"]}]},{"name":"Open Access Publication Fund of Philipps-Universit\u00e4t Marburg with support of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","award":["15\/2021"],"award-info":[{"award-number":["15\/2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mutations in MAGED2 cause transient Bartter syndrome characterized by severe renal salt wasting in fetuses and infants, which leads to massive polyhydramnios causing preterm labor, extreme prematurity and perinatal death. Notably, this condition resolves spontaneously in parallel with developmental increase in renal oxygenation. MAGED2 interacts with G-alpha-S (G\u03b1s). Given the role of G\u03b1s in activating adenylyl cyclase at the plasma membrane and consequently generating cAMP to promote renal salt reabsorption via protein kinase A (PKA), we hypothesized that MAGED2 is required for this signaling pathway under hypoxic conditions such as in fetuses. Consistent with that, under both physical and chemical hypoxia, knockdown of MAGED2 in renal (HEK293) and cancer (HeLa) cell culture models caused internalization of G\u03b1s, which was fully reversible upon reoxygenation. In contrast to G\u03b1s, cell surface expression of the \u03b22-adrenergic receptor, which is coupled to G\u03b1s, was not affected by MAGED2 depletion, demonstrating specific regulation of G\u03b1s by MAGED2. Importantly, the internalization of G\u03b1s due to MAGED2 deficiency significantly reduced cAMP generation and PKA activity. Interestingly, the internalization of G\u03b1s was blocked by preventing its endocytosis with dynasore. Given the role of E3 ubiquitin ligases, which can be regulated by MAGE-proteins, in regulating endocytosis, we assessed the potential role of MDM2-dependent ubiquitination in MAGED2 deficiency-induced internalization of G\u03b1s under hypoxia. Remarkably, MDM2 depletion or its chemical inhibition fully abolished G\u03b1s-endocytosis following MAGED2 knockdown. Moreover, endocytosis of G\u03b1s was also blocked by mutation of ubiquitin acceptor sites in G\u03b1s. Thus, we reveal that MAGED2 is essential for the cAMP\/PKA pathway under hypoxia to specifically regulate G\u03b1s endocytosis by blocking MDM2-dependent ubiquitination of G\u03b1s. This may explain, at least in part, the transient nature of Bartter syndrome caused by MAGED2 mutations and opens new avenues for therapy in these patients.<\/jats:p>","DOI":"10.3390\/cells11162546","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T23:44:25Z","timestamp":1660693465000},"page":"2546","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["MAGED2 Is Required under Hypoxia for cAMP Signaling by Inhibiting MDM2-Dependent Endocytosis of G-Alpha-S"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4839-9834","authenticated-orcid":false,"given":"Elie","family":"Seaayfan","sequence":"first","affiliation":[{"name":"University Children\u2019s Hospital, Philipps University, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sadiq","family":"Nasrah","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, Philipps University, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4400-3129","authenticated-orcid":false,"given":"Lea","family":"Quell","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, Philipps University, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5530-7016","authenticated-orcid":false,"given":"Maja","family":"Kleim","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, Philipps University, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Weber","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, Philipps University, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1883-1796","authenticated-orcid":false,"given":"Hemmo","family":"Meyer","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Duisburg-Essen, 45141 Duisburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2167-5766","authenticated-orcid":false,"given":"Kamel","family":"Laghmani","sequence":"additional","affiliation":[{"name":"Centre de Recherche des Cordeliers, Sorbonne Universit\u00e9, Inserm, Universit\u00e9 de Paris, CNRS, ERL8228, F-75006 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6499-5313","authenticated-orcid":false,"given":"Martin","family":"K\u00f6mhoff","sequence":"additional","affiliation":[{"name":"University Children\u2019s Hospital, Philipps University, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1056\/NEJMoa1507629","article-title":"Polyhydramnios, Transient Antenatal Bartter\u2019s Syndrome, and MAGED2 Mutations","volume":"374","author":"Laghmani","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1203\/00006450-197109000-00003","article-title":"Studies on the Circulation of the Previable Human Fetus","volume":"5","author":"Rudolph","year":"1971","journal-title":"Pediatric Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1056\/NEJM199503093321006","article-title":"Hypoxia of the renal medulla\u2014Its implications for disease","volume":"332","author":"Brezis","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/sj.ki.5000062","article-title":"Expression of hypoxia-inducible transcription factors in developing human and rat kidneys","volume":"69","author":"Bernhardt","year":"2006","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1007\/s00467-016-3333-5","article-title":"Role of hypoxia during nephrogenesis","volume":"31","author":"Hemker","year":"2016","journal-title":"Pediatr. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16121","DOI":"10.1074\/jbc.REV120.008029","article-title":"Emerging roles of the MAGE protein family in stress response pathways","volume":"295","author":"Chen","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/j.molcel.2010.08.029","article-title":"MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases","volume":"39","author":"Doyle","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1152\/physrev.00012.2016","article-title":"Ubiquitination and the Regulation of Membrane Proteins","volume":"97","author":"Foot","year":"2017","journal-title":"Physiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.1016\/j.cell.2021.04.011","article-title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome","volume":"184","author":"Huttlin","year":"2021","journal-title":"Cell"},{"key":"ref_10","first-page":"a011148","article-title":"The cyclic AMP pathway","volume":"4","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1152\/physrev.00053.2006","article-title":"Mouse models and the urinary concentrating mechanism in the new millennium","volume":"87","author":"Fenton","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Lv, Y., Zhang, Y., and Gao, H. (2014). Regulation of p53 Level by UBE4B in Breast Cancer. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090154"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/1878-0261.12592","article-title":"Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2","volume":"14","author":"Figueras","year":"2020","journal-title":"Mol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12559","DOI":"10.1073\/pnas.96.22.12559","article-title":"Identification of the endophilins (SH3p4\/p8\/p13) as novel binding partners for the \u03b21-adrenergic receptor","volume":"96","author":"Tang","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1002\/jat.3749","article-title":"The use of cobalt chloride as a chemical hypoxia model","volume":"39","year":"2019","journal-title":"J. Appl. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"745","DOI":"10.3892\/ol.2012.813","article-title":"Effect of mesenchymal stem cells on hypoxia-induced desensitization of \u03b22-adrenergic receptors in rat osteosarcoma cells","volume":"4","author":"Kido","year":"2012","journal-title":"Oncol. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e90240","DOI":"10.1172\/jci.insight.90240","article-title":"Hypoxia sensing through \u03b2-adrenergic receptors","volume":"1","author":"Cheong","year":"2016","journal-title":"JCI Insight"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/387296a0","article-title":"Mdm2 promotes the rapid degradation of p53","volume":"387","author":"Haupt","year":"1997","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8247","DOI":"10.1073\/pnas.1431613100","article-title":"Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor","volume":"100","author":"Girnita","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.cell.2015.06.043","article-title":"The BioPlex Network: A Systematic Exploration of the Human Interactome","volume":"162","author":"Huttlin","year":"2015","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/nature22366","article-title":"Architecture of the human interactome defines protein communities and disease networks","volume":"545","author":"Huttlin","year":"2017","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"305","DOI":"10.15252\/embr.201744465","article-title":"Regulation of the Mdm2\u2013p53 pathway by the ubiquitin E3 ligase MARCH7","volume":"19","author":"Zhao","year":"2018","journal-title":"EMBO Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.bbrc.2008.10.054","article-title":"G\u03b1q reduces cAMP production by decreasing G\u03b1s protein abundance","volume":"377","author":"Tang","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","unstructured":"Li, A., Gao, X., Ren, J., Jin, C., and Xue, Y. (2021, June 01). BDM-PUB: Computational Prediction of Protein Ubiquitination Sites with a Bayesian Discriminant Method. Available online: http:\/\/bdmpub.biocuckoo.org\/prediction.php."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1038\/bjc.2017.265","article-title":"MDM2 promotes epithelial-mesenchymal transition and metastasis of ovarian cancer SKOV3 cells","volume":"117","author":"Chen","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1091\/mbc.7.8.1225","article-title":"Activation-induced subcellular redistribution of Gs alpha","volume":"7","author":"Wedegaertner","year":"1996","journal-title":"Mol. Biol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/nchembio.206","article-title":"Sustained cyclic AMP production by parathyroid hormone receptor endocytosis","volume":"5","author":"Ferrandon","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27849","DOI":"10.1074\/jbc.M112.445098","article-title":"Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin","volume":"288","author":"Feinstein","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13477","DOI":"10.1073\/pnas.1708215114","article-title":"Galphas protein binds ubiquitin to regulate epidermal growth factor receptor endosomal sorting","volume":"114","author":"Li","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4556","DOI":"10.1038\/ncomms5556","article-title":"Galphas regulates the post-endocytic sorting of G protein-coupled receptors","volume":"5","author":"Rosciglione","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.tips.2009.04.001","article-title":"Shuttling and translocation of heterotrimeric G proteins and Ras","volume":"30","author":"Saini","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9470","DOI":"10.1021\/bi025533u","article-title":"Activation-induced subcellular redistribution of G alpha(s) is dependent upon its unique N-terminus","volume":"41","author":"Thiyagarajan","year":"2002","journal-title":"Biochemistry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1124\/mol.104.008342","article-title":"Beta-adrenergic receptor stimulation promotes G alpha s internalization through lipid rafts: A study in living cells","volume":"67","author":"Allen","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"44101","DOI":"10.1074\/jbc.M405151200","article-title":"Live cell imaging of Gs and the beta2-adrenergic receptor demonstrates that both alphas and beta1gamma7 internalize upon stimulation and exhibit similar trafficking patterns that differ from that of the beta2-adrenergic receptor","volume":"279","author":"Hynes","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1124\/mol.61.2.352","article-title":"Real-time visualization of a fluorescent G(alpha)(s): Dissociation of the activated G protein from plasma membrane","volume":"61","author":"Yu","year":"2002","journal-title":"Mol. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"42028","DOI":"10.18632\/oncotarget.5973","article-title":"Cancer-testis antigen MAGE-C2 binds Rbx1 and inhibits ubiquitin ligase-mediated turnover of cyclin E","volume":"6","author":"Hao","year":"2015","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Marcar, L., Ihrig, B., Hourihan, J., Bray, S.E., Quinlan, P.R., Jordan, L.B., Thompson, A.M., Hupp, T.R., and Meek, D.W. (2015). MAGE-A Cancer\/Testis Antigens Inhibit MDM2 Ubiquitylation Function and Promote Increased Levels of MDM4. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127713"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.molcel.2006.11.007","article-title":"New roles for beta-arrestins in cell signaling: Not just for seven-transmembrane receptors","volume":"24","author":"Lefkowitz","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e12582","DOI":"10.14814\/phy2.12582","article-title":"Placental oxygen transport estimated by the hyperoxic placental BOLD MRI response","volume":"3","author":"Sorensen","year":"2015","journal-title":"Physiol. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1055\/s-2007-969566","article-title":"Forskolin\u2014From an Ayurvedic Remedy to a Modern Agent","volume":"51","author":"Ammon","year":"1985","journal-title":"Planta Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1038\/oby.2005.162","article-title":"Body Composition and Hormonal Adaptations Associated with Forskolin Consumption in Overweight and Obese Men","volume":"13","author":"Godard","year":"2005","journal-title":"Obes. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/1550-2783-2-2-54","article-title":"Effects of coleus forskohlii supplementation on body composition and hematological profiles in mildly overweight women","volume":"2","author":"Henderson","year":"2005","journal-title":"J. Int. Soc. Sports Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1177\/147323000603400210","article-title":"Forskolin versus Sodium Cromoglycate for Prevention of Asthma Attacks: A Single-blinded Clinical Trial","volume":"34","author":"Trujillo","year":"2006","journal-title":"J. Int. Med. Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Salehi, B., Staniak, M., Czopek, K., Stepien, A., Dua, K., Wadhwa, R., Chellappan, D.K., Sytar, O., Brestic, M., and Bhat, N.G. (2019). The Therapeutic Potential of the Labdane Diterpenoid Forskolin. Appl. Sci., 9.","DOI":"10.3390\/app9194089"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"eaav4832","DOI":"10.1126\/sciadv.aav4832","article-title":"MAGE cancer-testis antigens protect the mammalian germline under environmental stress","volume":"5","author":"Montoya","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1245\/ASO.2006.12.011","article-title":"The role of genetic markers\u2014NAP1L1, MAGE-D2, and MTA1\u2014In defining small-intestinal carcinoid neoplasia","volume":"13","author":"Kidd","year":"2006","journal-title":"Ann. Surg. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1002\/cam4.1522","article-title":"A novel dual-marker expression panel for easy and accurate risk stratification of patients with gastric cancer","volume":"7","author":"Kanda","year":"2018","journal-title":"Cancer Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1002\/jso.21580","article-title":"Differential gene expression profile of MAGE family in taiwanese patients with colorectal cancer","volume":"102","author":"Chung","year":"2010","journal-title":"J. Surg. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.lungcan.2006.12.004","article-title":"Differential expression profile of MAGE family in non-small-cell lung cancer","volume":"56","author":"Tsai","year":"2007","journal-title":"Lung Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/s12943-019-1089-9","article-title":"Role of hypoxia in cancer therapy by regulating the tumor microenvironment","volume":"18","author":"Jing","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1038\/onc.2012.510","article-title":"The growing complexity of HIF-1alpha\u2019s role in tumorigenesis: DNA repair and beyond","volume":"32","author":"Rohwer","year":"2013","journal-title":"Oncogene"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nrc3521","article-title":"The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer","volume":"13","author":"Kufareva","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/gcc.22854","article-title":"Activating genomic alterations in the Gs alpha gene (GNAS) in 274694 tumors","volume":"59","author":"Tirosh","year":"2020","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"778814","DOI":"10.3389\/fped.2021.778814","article-title":"A Case Report and Literature Review of a Novel Mutation in the MAGED2 Gene of a Patient With Severe Transient Polyhydramnios","volume":"9","author":"Wu","year":"2021","journal-title":"Front. Pediatrics"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Karousis, E.D., and M\u00fchlemann, O. (2022). The broader sense of nonsense. Trends Biochem. Sci.","DOI":"10.1016\/j.tibs.2022.06.003"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/16\/2546\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:10:47Z","timestamp":1760141447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/16\/2546"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,16]]},"references-count":55,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["cells11162546"],"URL":"https:\/\/doi.org\/10.3390\/cells11162546","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,16]]}}}