An apoptotic signaling pathway in the interferon antiviral response mediated by RNase L and c-Jun NH2-terminal kinase.

Abstract

Cellular stress responses induced during viral infections are critical to the health and survival of organisms. In higher vertebrates, interferons (IFNs) mediate the innate antiviral response in part through the action of RNase L, a uniquely regulated enzyme. RNase L is activated by 5'-phosphorylated, 2'-5' oligoadenylates (2-5A) produced from IFN-inducible and double stranded RNA-dependent synthetases. We show that viral activation of the c-Jun NH2-terminal kinases (JNK) family of MAP kinases and viral induction of apoptosis are both deficient in mouse cells lacking RNase L. Also, JNK phosphorylation in response to 2-5A was greatly reduced in RNase L-/- mouse cells. In addition, 2-5A treatment of the human ovarian carcinoma cell line, Hey1b, resulted in specific ribosomal RNA cleavage products coinciding with JNK activation. Furthermore, suppression of JNK activity with the chemical inhibitor, SP600125, prevented apoptosis induced by 2-5A. In contrast, inhibition of alternative MAP kinases, p38 and ERK, failed to prevent 2-5A-mediated apoptosis. Short interfering RNA to JNK1/JNK2 mRNAs resulted in JNK ablation while also suppressing 2-5A-mediated apoptosis. Moreover, Jnk1-/- Jnk2-/- cells were highly resistant to the apoptotic effects of IFN and 2-5A. These findings suggest that JNK and RNase L function in an integrated signaling pathway during the IFN response that leads to elimination of virus-infected cells through apoptosis.

• Authors: Geqiang Li, Ying Xiang, Kanaga Sabapathy, Robert H Silverman
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 2 Pg. 1123-31 (Jan 09 2004) ISSN: 0021-9258 [Print] United States
• PMID: 14570908 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anthracenes
• RNA, Small Interfering
• pyrazolanthrone
• RNA
• Interferons
• Cycloheximide
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• Endoribonucleases
• 2-5A-dependent ribonuclease

Topics

• Animals
• Anthracenes (pharmacology)
• Apoptosis
• Blotting, Western
• Cell Line, Tumor
• Cell-Free System
• Cells, Cultured
• Cycloheximide (pharmacology)
• Dose-Response Relationship, Drug
• Endoribonucleases (metabolism)
• Enzyme Activation
• Humans
• In Situ Nick-End Labeling
• Interferons (metabolism)
• JNK Mitogen-Activated Protein Kinases
• Kinetics
• MAP Kinase Signaling System
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Biological
• Models, Genetic
• Phosphorylation
• Protein Binding
• RNA (metabolism)
• RNA, Small Interfering (metabolism)
• Ribosomes (metabolism)
• Signal Transduction
• Time Factors
• Transfection
• Viruses (metabolism)