A STUDY OF THE INTERFERON ANTIVIRAL MECHANISM - APOPTOSIS ACTIVATION BY THE 2-5A SYSTEM

The 2-5A system contributes to the antiviral effect of interferons thr ough the synthesis of 2-5A and its activation of the ribonuclease, RNa se L. RNase L degrades viral and cellular RNA after activation by uniq ue, 2'-5' phosphodiester-linked, oligoadenylates [2-5A, (pp)p5'A2'(P5' A2')](n), n greater than or equal to 2. Because both the 2-5A system a nd apoptosis can serve as viral defense mechanisms and RNA degradation occurs during both processes, we investigated the potential role of R Nase L in apoptosis. Overexpression of human RNase L by an inducible p romoter in NIH3T3 fibroblasts decreased cell viability and triggered a poptosis. Activation of endogenous RNase L, ape specifically with 2-5A or with dsRNA, induced apoptosis. Inhibition of RNase L with a domina nt negative mutant suppressed poly (I)poly (C)-induced apoptosis in in terferon-primed fibroblasts. Moreover, inhibition of RNase L suppresse d apoptosis induced by poliovirus. Thus, increased RNase L levels indu ced apoptosis and inhibition of RNase L activity blocked viral-induced apoptosis. Apoptosis may be one of the antiviral mechanisms regulated by the 2-5A system.