title: A study of the interferon antiviral mechanism: apoptosis activation by the 2-5A system.
abstract: 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.
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Castelli
authors.forename: B A
authors.initials: BA
authors.lastname: Hassel
authors.forename: K A
authors.initials: KA
authors.lastname: Wood
authors.forename: X L
authors.initials: XL
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Amemiya
authors.forename: M C
authors.initials: MC
authors.lastname: Dalakas
authors.forename: P F
authors.initials: PF
authors.lastname: Torrence
authors.forename: R J
authors.initials: RJ
authors.lastname: Youle
mesh_terms: D016475:3T3 Cells; D000227:Adenine Nucleotides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053938:DNA Fragmentation; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007372:Interferons / Q000502:physiology*; D051379:Mice; D009843:Oligoribonucleotides / Q000378:metabolism*; D017955:Poliovirus / Q000472:pathogenicity; D012330:RNA, Double-Stranded / Q000378:metabolism; D014162:Transfection; D014762:Viral Interference / Q000502:physiology*
chemical_list: D000227:Adenine Nucleotides; D009843:Oligoribonucleotides; D012330:RNA, Double-Stranded; C023505:2',5'-oligoadenylate; D007372:Interferons; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease