title: RNase L mediates transient control of the interferon response through modulation of the double-stranded RNA-dependent protein kinase PKR.
abstract: The transient control of diverse biological responses that occurs in response to varied forms of stress is often a highly regulated process. During the interferon (IFN) response, translational repression due to phosphorylation of eukaryotic initiation factor 2alpha, eIF2alpha, by the double-stranded RNA-dependent protein kinase, PKR, constitutes a means of inhibiting viral replication. Here we show that the transient nature of the IFN response against acute viral infections is regulated, at least in part, by RNase L. During the IFN antiviral response in RNase L-null cells, PKR mRNA stability was enhanced, PKR induction was increased, and the phosphorylated form of eIF2alpha appeared with extended kinetics compared with similarly treated wild type cells. An enhanced IFN response in RNase L-null cells was also demonstrated by monitoring inhibition of viral protein synthesis. Furthermore, ectopic expression of RNase L from a plasmid vector prevented the IFN induction of PKR. These results suggest a role for RNase L in the transient control of the IFN response and possibly of other cytokine and stress responses.
authors.affiliation: Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia. khabar@kfshrc.edu.sa
authors.forename: Khalid S A
authors.initials: KS
authors.lastname: Khabar
authors.forename: Yunus M
authors.initials: YM
authors.lastname: Siddiqui
authors.forename: Fahad
authors.initials: F
authors.lastname: al-Zoghaibi
authors.forename: Latifa
authors.initials: L
authors.lastname: al-Haj
authors.forename: Mohammed
authors.initials: M
authors.lastname: Dhalla
authors.forename: Aimin
authors.initials: A
authors.lastname: Zhou
authors.forename: Beihua
authors.initials: B
authors.lastname: Dong
authors.forename: Mark
authors.initials: M
authors.lastname: Whitmore
authors.forename: Jayashree
authors.initials: J
authors.lastname: Paranjape
authors.forename: Mohammed N
authors.initials: MN
authors.lastname: Al-Ahdal
authors.forename: Futwan
authors.initials: F
authors.lastname: Al-Mohanna
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
mesh_terms: D000818:Animals; D002460:Cell Line; D004722:Endoribonucleases / Q000378:metabolism*; D007372:Interferons / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D012330:RNA, Double-Stranded / Q000378:metabolism*; D014162:Transfection; D014764:Viral Proteins / Q000096:biosynthesis; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D012330:RNA, Double-Stranded; D014764:Viral Proteins; D007372:Interferons; D019892:eIF-2 Kinase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease