title: 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.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Arindam
authors.initials: A
authors.lastname: Chakrabarti
authors.forename: Babal Kant
authors.initials: BK
authors.lastname: Jha
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D003711:Demyelinating Diseases / Q000517:prevention & control; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D012330:RNA, Double-Stranded / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014777:Virus Diseases / Q000276:immunology / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease