Membrane receptors for interferon.

Specific cell membrane receptors for interferon have been postulated based on a variety of different observations, such as the following: trypsin treatment of monkey-mouse hybrid cells preferentially destroys sensitivity to primate interferon (9); syngeneic mice immunized with human-mouse hybrid cells develop surface-directed antibodies, which only block antiviral action of human interferon (24); interferon covalently bound to Sepharose beads retains its antiviral activity despite the fact that diameters of the beads are several times those of the cells (1,10,19); cells challenged with polyl:C to produce interferon do not develop resistance to viral infection in the presence of interferon antiserum (30). Interferon has a strong and specific affinity for the carbohydrate side chain of cell membrane gangliosides. Preincubation of Sepharose-bound interferon with gangliosides inhibits antiviral activity in the following order of potency: GM2 greater than or equal to GTl greater than GMl greater than or equal to GDla (3). Derivatives of GM2 lacking either terminal N-acetyl-galactosamine or terminal N-acetyl-neuraminic acid are not (or very little) inhibitory; in addition, binding to gangliosides is reversed by N-acetyl-neuraminyl-lactose, the trisaccharide common to all gangliosides. These data clearly demonstrate interferon's specificity for the carbohydrate moiety of the ganglioside molecule (6). Phaeseolus vulgaris lectin, which blocks antiviral action of interferon (4), also prevents binding of interferon to ganglioside-Sepharose affinity columns (2). Many substances of known affinity for gangliosides likewise inhibit action of interferon. These include cholera (15) and tetanus toxins (2), thyrotropin (5,23) and human chorionic gonadotropin (5). Although a more general effect on the state of the membrane or on cellular metabolism by these substances cannot be ruled out, competition for interferon binding sites appears to be the most plausible explanation. Increased sensitivity of certain transformed cells to interferon upon uptake of exogenous gangliosides not only supports the concept that these glycolipids are involved in binding of interferon to the membrane, but furthermore points to the importance of interferon-ganglioside interaction for triggering of the antiviral response (29).