New Insights into the Role of RNase L in Innate Immunity

Abstract

The interferon (IFN)-inducible 2 0 -5 0 -oligoadenylate synthetase (OAS)/RNase L pathway blocks infections by some types of viruses through cleavage of viral and cellular single-stranded RNA. Viruses induce type I IFNs that initiate signaling to the OAS genes. OAS proteins are pathogen recognition receptors for the viral pathogenassociated molecular pattern, double-stranded RNA. Double-stranded RNA activates OAS to produce p x 5 0 A(2 0 p5 0 A) n ; x ¼ 1-3; n > 2 (2-5A) from ATP. Upon binding 2-5A, RNase L is converted from an inactive monomer to a potently active dimeric endoribonuclease for single-stranded RNA. RNase L contains, from N-to Cterminus, a series of 9 ankyrin repeats, a linker, several protein kinase-like motifs, and a ribonuclease domain homologous to Ire1 (involved in the unfolded protein response). In the past few years, it has become increasingly apparent that RNase L and OAS contribute to innate immunity in many ways. For example, small RNA cleavage products produced by RNase L during viral infections can signal to the retinoic acid-inducible-I like receptors to amplify and perpetuate signaling to the IFN-b gene. In addition, RNase L is now implicated in protecting the central nervous system against viral-induced demyelination. A role in tumor suppression was inferred by mapping of the RNase L gene to the hereditary prostate cancer 1 (HPC1) gene, which in turn led to discovery of the xenotropic murine leukemia-related virus. A broader role in innate immunity is suggested by involvement of RNase L in cytokine induction and endosomal pathways that suppress bacterial infections. These newly described findings about RNase L could eventually provide the basis for developing broad-spectrum antimicrobial drugs.

Apoptosis Induced by Mammalian Reovirus Is Beta Interferon (IFN) Independent and Enhanced by IFN Regulatory Factor 3- and NF-κB-Dependent Expression of Noxa

“…For example, protein kinase R (PKR) is activated by dsRNA and phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2␣), blocking translation initiation (61). The enzyme 2=-5=-oligoadenylate synthase (2=5=OAS) also is activated by dsRNA to produce 2=-5=-adenylic acid, which stimulates RNase L to degrade cellular RNA (11). These and other mechanisms prevent virus replication in infected cells and prime neighboring cells to enter a refractory antiviral state.…”

Rustless translation

“…It was described in 1995 as RNase-L inhibitor (RLI1) on the basis of its coimmunoprecipitation with RNase-L and inhibitory effect on RNase-L mediated RNA degradation (Bisbal et al , 1995 ). RNase-L is an interferon-dependent polysome-associated antiviral defense enzyme that is activated by 2 ′ -5 ′ oligoadenylates and degrades mRNA and single-stranded viral RNA in virus infected cells (Silverman , 2007 ), but also has a variety of additional functions (Chakrabarti et al , 2011 ). In 2002, ABCE1 was found to be required for the assembly of immature HIV-1 capsids and it has been suggested that it accounts for the ATP dependence of the rather poorly understood capsid assembly process (Zimmerman et al , 2002 ).…”

Single Nucleotide Polymorphism in Inflammatory Gene RNASEL Predicts Outcome After Radiation Therapy for Localized Prostate Cancer

“…RNASEL is a putative tumor-suppressing enzyme that may inhibit growth and proliferation and induce apoptosis (10)(11)(12), and is implicated in the cleavage of viral RNA and the interferonmediated immune response (13). Polymorphisms in RNASEL, located on chromosome 1q25, have been inconsistently linked to hereditary and general prostate cancer risk (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”