Placental syncytins: Genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins.
We have previously demonstrated that the envelope proteins of a murine and primate retrovirus are immunosuppressive in vivo. This property was manifested by the ability of the proteins, when expressed by allogeneic tumor cells normally rejected by engrafted mice, to have the env-expressing cells escape (at least transiently) immune rejection. Here, we analyzed the immunosuppressive activity of the human and murine syncytins. These are envelope genes from endogenous retroviruses independently coopted by ancestral hosts, conserved in evolution, specifically expressed in the placenta, and with a cell-cell fusogenic activity likely contributing to placenta morphogenesis. We show that in both humans and mice, one of the two syncytins (human syncytin-2 and mouse syncytin-B) is immunosuppressive and, rather unexpectedly, the other (human syncytin-1 and mouse syncytin-A) is not (albeit able to induce cell-cell fusion). Delineation of the immunosuppressive domain by deletion analysis, combined with a comparison between immunosuppressive and nonimmunosuppressive sequences, allowed us to derive a mutation rule targeted to specific amino acids, resulting in selective switch from immunosuppressive to nonimmunosuppressive envelope proteins and vice versa. These results unravel a critical function of retroviral envelopes, not necessarily "individually" selected for in the retrovirus endogenization process, albeit "tandemly" conserved in evolution for the syncytin pairs in primates and Muridae. Selective inactivation of immunosuppression, under conditions not affecting fusogenicity, should be important for understanding the role of this function in placental physiology and maternofetal tolerance.
Mangeney
Marianne
M
Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, Unité Mixte de Recherche 8122, Centre National de la Recherche Scientifique, Institut Gustave Roussy, F-94805 Villejuif, France.
Renard
Martial
M
Schlecht-Louf
Géraldine
G
Bouallaga
Isabelle
I
Heidmann
Odile
O
Letzelter
Claire
C
Richaud
Aurélien
A
Ducos
Bertrand
B
Heidmann
Thierry
T
D000595:Amino Acid Sequence; D000818:Animals; D020077:Endogenous Retroviruses; D005260:Female; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010920:Placenta / Q000276:immunology*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology*
C518353:ERVFRD-1 protein, human; D015686:Gene Products, env; D011257:Pregnancy Proteins; D014760:Viral Fusion Proteins; C405335:syncytin; C497515:syncytin-B protein, mouse