{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:37:52Z","timestamp":1787618272161,"version":"build-2736575974"},"reference-count":66,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"19","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,5,9]]},"abstract":"<jats:p>Syncytin-1 and Syncytin-2 are envelope glycoproteins encoded by human endogenous retroviruses that have been exapted for the fusion of cytotrophoblast cells into syncytiotrophoblasts during placental development. Pregnancy complications like preeclampsia are associated with altered expression of interferon-stimulated genes, including guanylate-binding protein 5 (GBP5). Here, we show that misdirected antiviral activity of GBP5 impairs processing and activation of Syncytin-1. In contrast, the proteolytic activation of Syncytin-2 is not affected by GBP5, and its fusogenic activity is only modestly reduced. Mechanistic analyses revealed that Syncytin-1 is mainly cleaved by the GBP5 target furin, whereas Syncytin-2 is also efficiently processed by the proprotein convertase subtilisin\/kexin type 7 (PCSK7) and thus resistant to GBP5-mediated restriction. Mutational analyses mapped PCSK7 processing of Syncytin-2 to a leucine residue upstream of the polybasic cleavage site. In summary, we identified an innate immune mechanism that impairs the activity of a co-opted endogenous retroviral envelope protein during pregnancy and may potentially contribute to the pathogenesis of pregnancy disorders.<\/jats:p>","DOI":"10.1126\/sciadv.adt5388","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T17:58:56Z","timestamp":1746640736000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":9,"title":["Inhibition of placental trophoblast fusion by guanylate-binding protein 5"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9192-5866","authenticated-orcid":true,"given":"Veronika","family":"Krchlikova","sequence":"first","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3595-7107","authenticated-orcid":true,"given":"Elisabeth","family":"Braun","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Weiss","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8708-606X","authenticated-orcid":true,"given":"Krystof","family":"Stafl","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6345-906X","authenticated-orcid":true,"given":"Lukas","family":"Jech","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4591-0513","authenticated-orcid":true,"given":"Smitha Srinivasachar","family":"Badarinarayan","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."},{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9630-7100","authenticated-orcid":true,"given":"Rishikesh","family":"Lotke","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0627-2560","authenticated-orcid":true,"given":"Martin","family":"Travnicek","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Baur","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9151-2032","authenticated-orcid":true,"given":"Paul","family":"Stark","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabell","family":"Haussmann","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueshuang","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Petersen","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Cui","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2870-0733","authenticated-orcid":true,"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca M.","family":"F\u00e4ger","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Reisinger","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2625-5322","authenticated-orcid":true,"given":"Kenzo","family":"Tokunaga","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0096-4948","authenticated-orcid":true,"given":"Oya","family":"Cing\u00f6z","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Institute of Virology, Berlin, Germany."},{"name":"MRC\u2013University of Glasgow, Centre for Virus Research (CVR), Glasgow, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8682-1779","authenticated-orcid":true,"given":"Konstantin M. J.","family":"Sparrer","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany."},{"name":"German Center for Neurodegenerative Diseases (DZNE), Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7939-289X","authenticated-orcid":true,"given":"Madhuri S.","family":"Salker","sequence":"additional","affiliation":[{"name":"Research Institute for Women\u2019s Health, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiri","family":"Hejnar","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7052-2360","authenticated-orcid":true,"given":"Frank","family":"Kirchhoff","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9872-3041","authenticated-orcid":true,"given":"Katerina","family":"Trejbalova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7665-0040","authenticated-orcid":true,"given":"Daniel","family":"Sauter","sequence":"additional","affiliation":[{"name":"Institute for Medical Virology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0189-2"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/gtc.12278"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2132646100"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.7.3321-3329.2000"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.108.069765"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0807413105"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.13.6442-6452.2002"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-023-08658-0"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03104-6"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41211"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioy049"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0698-6"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.07.025"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.65243"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw7733"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.AC119.010611"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gah070"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.163428"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1627473"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmq007"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2020.03.039"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.47162\/RJME.62.4.10"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13503"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-9-107"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/926875"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature15399"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature15400"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3956"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.29445"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.04.063"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-10-111"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260419"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2407519121"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66966"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0225062"},{"key":"e_1_3_2_37_2","first-page":"767","article-title":"Severe pre-eclampsia is associated with alterations in cytotrophoblasts of the smooth chorion","volume":"144","author":"Garrido-Gomez T.","year":"2017","unstructured":"T. Garrido-Gomez, K. Ona, M. Kapidzic, M. Gormley, C. Simon, O. Genbacev, S. J. Fisher, Severe pre-eclampsia is associated with alterations in cytotrophoblasts of the smooth chorion. Development 144, 767\u2013777 (2017).","journal-title":"Development"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1080\/14767058.2018.1533949"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2023.116611"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14721"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X19666210211150856"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9255"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa832"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01351-24"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2021.02.022"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.02.019"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-204-5_3"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.7b01124"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1021\/cb500087x"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2212577120"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.08.014"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jogoh.2021.102198"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.7754\/Clin.Lab.2021.210117"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2017.08.012"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1385473"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2012.12.001"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3889"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.752186"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-9-158"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03898-z"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.3390\/v11111011"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02086-24"},{"key":"e_1_3_2_63_2","doi-asserted-by":"crossref","unstructured":"S. Wang W. Li L. Wang S. K. Tiwari W. Bray L. Wu N. Li H. Hui A. E. Clark Q. Zhang L. Zhang A. F. Carlin T. M. Rana Interferon-inducible guanylate-binding protein 5 inhibits replication of multiple viruses by binding to the oligosaccharyltransferase complex and inhibiting glycoprotein maturation. bioRxiv 591800 [Preprint] (2024). https:\/\/doi.org\/10.1101\/2024.05.01.591800.","DOI":"10.1101\/2024.05.01.591800"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.11.8463-8471.1998"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1385\/JMN:22:1-2:5"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00182-10"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.05.002"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adt5388","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T18:00:42Z","timestamp":1746640842000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adt5388"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,9]]},"references-count":66,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2025,5,9]]}},"alternative-id":["10.1126\/sciadv.adt5388"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adt5388","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,9]]},"assertion":[{"value":"2024-09-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadt5388"}}