New insights into the role of RNase L in innate immunity

Abstract

The interferon (IFN)-inducible 2'-5'-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 pathogen-associated molecular pattern, double-stranded RNA. Double-stranded RNA activates OAS to produce p(x)5'A(2'p5'A)(n); x = 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 C-terminus, 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-β 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.

FIG. 1.

Role of RNase L in innate immunity against viruses and bacteria. The diagram illustrates how RNase L is activated in response to viral double-stranded RNA activating OAS to produce 2-5A from ATP. The RNase L domains shown are “A,” ARD; “K,” PK-like; and “N,” RNASE. 2-5A binding to the ARD causes inactive RNase L monomers to form activated dimers that degrade viral and cellular single-stranded RNA. RNA cleavage products activate RIG-I to amplify production of IFN-β. Bacterial infections signal through RNase L to inhibit Cathepsin E synthesis enhancing levels of lysosome-associated membrane proteins, LAMP 1 and 2, required for the terminal step in phagosome maturation and destruction of the microbial contents. NOD2 interacts with OAS2, whereas NOD2 overexpression leads to enhanced RNase L activity in the presence of double-stranded RNA. NOD2 responds to bacterial MDP triggering NF-κB activation contributing to type I IFN, IL-1β and TNF-α synthesis. ARD, ankyrin repeat domain; IFN, interferon; MDP, muramyl dipeptide; NOD2, nucleotide-binding and oligomerization domain-2; OAS, 2′-5′-oligoadenylate synthetase; PK, protein kinase; RIG-I, retinoic acid-inducible gene-I.

FIG. 2.

Domain structure of RNase L. The main structural and functional domains of RNase L are shown, including ankyrin repeat domain, ARD; protein kinase-like domain, PK; ribonuclease domain, RNASE; kinase-extension-nuclease domain, KEN, and peptide N-glycanase/UBA or UBX-containing protein domain, PUG or PUB. The region responsible for binding 2-5A is indicated.