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.
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15 September 1997
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September 15 1997
A Study of the Interferon Antiviral Mechanism: Apoptosis Activation by the 2–5A System
JoAnn C. Castelli,
JoAnn C. Castelli
From the *Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; ‡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
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Bret A. Hassel,
Bret A. Hassel
From the *Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; ‡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
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Katherine A. Wood,
Katherine A. Wood
From the *Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; ‡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
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Xiao-Ling Li,
Xiao-Ling Li
From the *Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; ‡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
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Kei Amemiya,
Kei Amemiya
From the *Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; ‡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
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Marinos C. Dalakas,
Marinos C. Dalakas
From the *Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; ‡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
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Paul F. Torrence,
Paul F. Torrence
From the *Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; ‡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
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Richard J. Youle
Richard J. Youle
From the *Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; ‡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
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JoAnn C. Castelli,
Bret A. Hassel,
Katherine A. Wood,
Xiao-Ling Li,
Kei Amemiya,
Marinos C. Dalakas,
Paul F. Torrence,
Richard J. Youle
From the *Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; ‡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
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: [email protected]
Received:
May 12 1997
Revision Received:
June 30 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 186 (6): 967–972.
Article history
Received:
May 12 1997
Revision Received:
June 30 1997
Citation
JoAnn C. Castelli, Bret A. Hassel, Katherine A. Wood, Xiao-Ling Li, Kei Amemiya, Marinos C. Dalakas, Paul F. Torrence, Richard J. Youle; A Study of the Interferon Antiviral Mechanism: Apoptosis Activation by the 2–5A System . J Exp Med 15 September 1997; 186 (6): 967–972. doi: https://doi.org/10.1084/jem.186.6.967
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