Syncytin-1, syncytin-2 and suppressyn in human health and disease

Abstract

In this review, we summarized the results of experimental and clinical studies about three human endogenous retroviruses and their products-syncytin-1, syncytin-2, and suppressyn in human physiology and pathophysiology. We summed up the described connection with various pathological processes and diseases, mainly with pregnancy-induced hypertensive diseases such as preeclampsia, oncogenesis, gestational trophoblastic disease, and multiple sclerosis. Supposed mechanisms of action and the potential of clinical applications are also described.

Keywords: Gestational trophoblastic disease; HERVs; Preeclampsia; Suppressyn; Syncytin-1; Syncytin-2.

Fig. 1

Evolutionary origin of human endogenous retroviral genes (HERVs). Retroviruses can infect somatic cells of the host and the virus can then spread in the population (horizontal transmission). Retroviral infection of host germ cells potentially results in the integration of viral DNA into the host genome. Integrated sequences display typical proviral structure with two LTR flanking both ends and gag, env, pol viral genes. In the case of germ cell infections, these sequences can be vertically inherited in Mendelian fashion (vertical transmission) and preserved in some form during evolution to provide a selective advantage. Mutations in proviral sequences have caused these viruses to become unfunctional. However, in rare cases during evolution, the ORFs of some of the viral genes have become conserved and adopted several physiological functions, mainly in placenta formation. LTR, long terminal repeat; SUPYN, suppressyn. Created in biorender.com

Fig. 2

Expression levels of selected HERVs and their receptors in placental tissue. Chorionic villi and trophoblast populations in a 28-gestational-week placenta with a schematic cartoon representation of chorionic villus (left). Expression levels of genes coding syncytin-1 (ERVW-1), syncytin-2 (ERVFRD-1), suppressyn (ERVH48-1), and their receptors (SLC1A5, SLC1A4, MFSD2A) in trophoblast populations (right); nTPM, normalized protein-coding transcripts per million. Expression data from proteinatlas.org. The placenta was stained by hematoxylin and eosin. An image of the placenta was taken by light microscope Axio Vert. A1 in software Axio Vision 4.8 (Zeiss) by Lajos Gergely, MD (Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovak Republic). Created in biorender.com

Fig. 3

Structure and roles of syncytins in the human body. Syncytin-1 and syncytin-2 are both involved in several physiological (left) and pathological (right) processes. In terms of structure, both genes display SU and TM units together with FP, ISD, MAD, and CYT domains. CXXC and CX6CC motives are essential for the creation of disulfide bonds between TM and SU units in protein. Syncytin-1 is involved in placenta formation (a), gamete fusion (b), prevention of viral infections (c), osteoclast formation (d), myotube formation (e), and feto-maternal immune tolerance (f). Syncytin-2 is involved in placenta formation (a) and feto-maternal immune tolerance (f). In terms of the pathogenesis of disease, syncytins were found to be involved in (g) preeclampsia, (h) tumorigenesis, (i) gestational trophoblastic disease, (j) multiple sclerosis, and (k) gestational diabetes. SU, surface unit; TM, transmembrane unit; FP, fusion peptide; ISD, immunosuppressive domain; MAD, membrane anchorage domain; CYT, cytoplasmic domain. Protein structures were generated by AlphaFold [97]. Molecular graphics performed with UCSF ChimeraX (rbvi.ucsf.edu/chimerax). Created in biorender.com

Fig. 4

Confirmed and potential interactions of syncytin-1, syncytin-2, and suppressyn. Syncytin-1, located in the cellular membrane, interacts with both ASCT-1 and ASCT-2 receptors, resulting in cell–cell fusion. a Syncytin-2, also localized in the cellular membrane, binds to the MFSD2A receptor, promoting cell–cell fusion. b Suppressyn, found in both intracellular and secreted forms, binds to the ASCT-2 receptor, inhibiting cell–cell fusion. c ASCT receptors function mainly as sodium-coupled amino acid transporters, whereas MFSD2A acts as a sodium-dependent LPC symporter. ASCT-2 also represents a binding site for gammaretroviruses feline endogenous retrovirus RD-114, baboon endogenous retrovirus, Reticuloendotheliosis virus A (REV-A), spleen necrosis virus (SNV), and betaretroviruses simian retrovirus serotypes 1–5 (SRV). d Syncytins potentially interact with CD4, CD46, and TNFRS receptors, which can result in activation of various signaling cascades. e Inside the nucleus, syncytin-2 potentially interacts with the GCM1 transcription factor. f These interactions were predicted by the https://string-db.org/ algorithm. Functions of ASCT-1, ASCT-2, and MFSD2A receptors were derived from https://uniprot.org/. Created in biorender.com