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.

Charité Universitätsmedizin Berlin Institute of Virology Berlin Germany

College of Pharmacy Chongqing Medical University Chongqing China

Department of Pathology National Institute of Infectious Diseases Tokyo Japan

German Center for Neurodegenerative Diseases Ulm Germany

Institute for Medical Virology University Hospital Tübingen Tübingen Germany

Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czechia

Institute of Molecular Virology Ulm University Medical Center Ulm Germany

MRC University of Glasgow Centre for Virus Research Glasgow UK

Research Institute for Women's Health University Hospital Tübingen Tübingen Germany

Zobrazit více v PubMed

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