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 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.
Castelli
J C
JC
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Hassel
B A
BA
Wood
K A
KA
Li
X L
XL
Amemiya
K
K
Dalakas
M C
MC
Torrence
P F
PF
Youle
R J
RJ
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*
D000227:Adenine Nucleotides; D009843:Oligoribonucleotides; D012330:RNA, Double-Stranded; C023505:2',5'-oligoadenylate; D007372:Interferons; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease