TY  - JOUR
AU  - Krchlikova, Veronika
AU  - Braun, Elisabeth
AU  - Weiss, Johanna
AU  - Stafl, Krystof
AU  - Jech, Lukas
AU  - Badarinarayan, Smitha Srinivasachar
AU  - Lotke, Rishikesh
AU  - Travnicek, Martin
AU  - Baur, Charlotte
AU  - Stark, Paul
AU  - Haussmann, Isabell
AU  - Lu, Yueshuang
AU  - Petersen, Moritz
AU  - Cui, Wen
AU  - Wang, Wei
AU  - Fäger, Bianca M
AU  - Reisinger, Hannah
AU  - Tokunaga, Kenzo
AU  - Cingöz, Oya
AU  - Sparrer, Konstantin M J
AU  - Salker, Madhuri S
AU  - Hejnar, Jiri
AU  - Kirchhoff, Frank
AU  - Trejbalova, Katerina
AU  - Sauter, Daniel
TI  - Inhibition of placental trophoblast fusion by guanylate-binding protein 5.
JO  - Science advances
VL  - 11
IS  - 19
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DZNE-2025-00596
SP  - eadt5388
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Trophoblasts: metabolism
KW  - Trophoblasts: cytology
KW  - Female
KW  - Pregnancy
KW  - Pregnancy Proteins: metabolism
KW  - Pregnancy Proteins: genetics
KW  - GTP-Binding Proteins: metabolism
KW  - GTP-Binding Proteins: genetics
KW  - Furin: metabolism
KW  - Placenta: metabolism
KW  - Placenta: cytology
KW  - Gene Products, env: metabolism
KW  - Gene Products, env: genetics
KW  - Cell Fusion
KW  - Pregnancy Proteins (NLM Chemicals)
KW  - GTP-Binding Proteins (NLM Chemicals)
KW  - Furin (NLM Chemicals)
KW  - Gene Products, env (NLM Chemicals)
KW  - syncytin (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40333975
C2  - pmc:PMC12057675
DO  - DOI:10.1126/sciadv.adt5388
UR  - https://pub.dzne.de/record/278563
ER  -