RNase-L-dependent destabilization of interferon-induced mRNAs. A role for the 2-5A system in attenuation of the interferon response.
The 2-5A system is an interferon-regulated RNA degradation pathway with antiviral, growth-inhibitory, and pro-apoptotic activities. RNase-L mediates the antiviral activity through the degradation of viral RNAs, and the anticellular effects of the 2-5A system are thought to be similarly mediated through the degradation of cellular transcripts. However, specific RNase-L-regulated cellular RNAs have not been identified. To isolate candidate RNase-L substrates, differential display was used to identify mRNAs that exhibited increased expression in RNase-L-deficient N1E-115 cells as compared with RNase-L-transfected cells. A novel interferon-stimulated gene encoding a 43-kDa ubiquitin-specific protease, designated ISG43, was identified in this screen. ISG43 expression is induced by interferon and negatively regulated by RNase-L. ISG43 induction is a primary response to interferon treatment and requires a functional JAK/STAT signaling pathway. The kinetics of ISG43 induction were identical in wild type and RNase-L knock-out fibroblasts; however, the decline in ISG43 mRNA following interferon treatment was markedly attenuated in RNase-L knock-out fibroblasts. The delayed shut-off kinetics of ISG43 mRNA corresponded to an increase in its half-life in RNase-L-deficient cells. ISG15 mRNA also displayed RNase-L-dependent regulation. These findings identify a novel role for the 2-5A system in the attenuation of the interferon response.
Li
X L
XL
Greenebaum Cancer Center, Program in Oncology, University of Maryland, Baltimore, Maryland 21201, USA.
Blackford
J A
JA
Judge
C S
CS
Liu
M
M
Xiao
W
W
Kalvakolanu
D V
DV
Hassel
B A
BA
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D064570:Ubiquitin-Specific Proteases; D014452:Ubiquitins / Q000378:metabolism
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; D014452:Ubiquitins; D007372:Interferons; D020928:Mitogen-Activated Protein Kinases; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases