RESUMEN
The 2'-5' oligoadenylate synthetase (OAS) proteins are traditionally considered intracellular antiviral proteins. However, several studies demonstrate a correlation between the concentration of freely circulating OAS protein in sera from hepatitis C patients and their clinical prognosis. Here we demonstrate that extracellular OAS1 enters into cells and possesses a strong antiviral activity, both in vitro and in vivo, which is independent of RNase L. The OAS protein directly inhibits viral proliferation and does not require the activation of known antiviral signaling pathways. We propose that OAS produced by cells infected with viruses is released to the extracellular space, where it acts as a paracrine antiviral agent. Thus, the OAS protein represents the first direct antiviral compound released by virus-infected cells.
Asunto(s)
2',5'-Oligoadenilato Sintetasa/inmunología , Antivirales/inmunología , Endorribonucleasas/inmunología , Espacio Extracelular/enzimología , Interacciones Huésped-Patógeno , Virosis/enzimología , Virosis/inmunología , Virus/inmunología , 2',5'-Oligoadenilato Sintetasa/genética , Animales , Línea Celular , Endorribonucleasas/genética , Espacio Extracelular/inmunología , Humanos , Inmunidad Innata , Ratones , Ratones Endogámicos C57BL , Virosis/virología , Fenómenos Fisiológicos de los VirusRESUMEN
Interferon-lambda (IFN-lambda) is an antiviral cytokine that signals through a distinct receptor complex, composed of the IFN-lambdaR1 and interleukin-10R2 (IL-10R2) receptor chains. We have determined the crystal structure of human IFN-lambda3 and characterized the interaction with its receptor complex through structure-based site-directed mutagenesis. The ability of IFN-lambda3 mutants to signal was determined by measuring the antiviral activity and induced STAT2 phosphorylation. In conclusion, our data show that, although IFN-lambda is functionally an interferon, it is clearly structurally related to members of the IL-10 family. In particular, we found an interesting similarity between IFN-lambda and IL-22, and we suggest that IFN-lambda and IL-22 possess parallel functions, protecting epithelial tissue against viral and bacterial infections, respectively.