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© The Rockefeller University Press, 0022-1007/1997/9/967/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 6, September 15, 1997 967-972

Brief Definitive Report

A Study of the Interferon Antiviral Mechanism: Apoptosis Activation by the 2–5A System

JoAnn C. Castelli*, Bret A. Hassel{ddagger}, Katherine A. Wood*, Xiao-Ling Li{ddagger}, Kei Amemiya§, Marinos C. Dalakas§, Paul F. Torrence||, and Richard J. Youle*

From the * Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; {ddagger} University of Maryland at Baltimore Cancer Center, Department of Microbiology and Immunology, Baltimore, Maryland 21201; § Neuromuscular Diseases Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; and || Section on Biomedical Chemistry, Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

The 2–5A system contributes to the antiviral effect of interferons through the synthesis of 2–5A and its activation of the ribonuclease, RNase L. RNase L degrades viral and cellular RNA after activation by unique, 2'–5' phosphodiester-linked, oligoadenylates [2–5A, (pp)p5' A2'(P5'A2')]n, n >=2. Because both the 2–5A system and apoptosis can serve as viral defense mechanisms and RNA degradation occurs during both processes, we investigated the potential role of RNase L in apoptosis. Overexpression of human RNase L by an inducible promoter in NIH3T3 fibroblasts decreased cell viability and triggered apoptosis. Activation of endogenous RNase L, specifically with 2–5A or with dsRNA, induced apoptosis. Inhibition of RNase L with a dominant negative mutant suppressed poly (I)·poly (C)–induced apoptosis in interferon-primed fibroblasts. Moreover, inhibition of RNase L suppressed apoptosis induced by poliovirus. Thus, increased RNase L levels induced 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.

Address correspondence to Dr. Richard J. Youle, Biochemistry Section, Surgical Neurology Branch, NINDS/NIH, Bethesda, MD 20892-1414. Phone: 301-496-6628; FAX: 301-402-0380 E-mail: youle{at}helix.nih.gov


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