The (2-5A)-RNase L pathway is an important component of interferon (IFN) ac
tion. Its central role in the antiviral effect of IFN against Picornavirida
e has been clearly demonstrated. We have characterized and cloned a new com
ponent of this pathway, the RNase L inhibitor (RLI). RLI is a cellular prot
ein whose mRNA is not regulated by IFN but is induced by viruses, such as e
ncephalomyocarditis virus (EMCV). RLI inhibits RNase L during the time cour
se of EMCV infection, and overexpression of RLI in HeLa cells partially rev
erses the antiviral action of IFN against EMCV. The replicative complexes o
f several viruses consist of double-stranded RNA structures. These dsRNAs c
ould activate gene transcription as demonstrated for IFNs and could be resp
onsible for RLI induction. We describe the increased expression of RLI mRNA
and RLI protein induced by synthetic dsRNAs, such as poly(I):poly(C). This
induction gives rise to an inhibition of the 2-5A-binding activity of RNas
e L. The inhibition of RNase L activity is transcient, probably due to the
rapid turnover of RLI protein.