A novel RNA molecular signature for activation of 2'-5' oligoadenylate synthetase-1

• Type of Material: Article
• Authors: Virginia K. Vachon, Emory University; Brenda M. Calderon, Emory University; Graeme L Conn, Emory University
• Language: English
• Date: 2014-10-01
• Publisher: Oxford University Press
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2014.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/nar/gku1289
• Title of Journal or Parent Work: Nucleic Acids Research
• Volume: 43
• Issue: 1
• Start Page: 544
• End Page: 552
• Grant/Funding Information: National Institutes of Health-National Institute of Allergy and Infectious Diseases [R21-AI097803]; National Institutes of Health-National Institute of General Medical Science [T32-GM008367]; Emory University Research Council [URC 2010050]. Funding for open access charge: Department of Biochemistry, Emory University.
• Keywords: Humans; RNA, Double-Stranded; RNA, Viral; Nucleotide Motifs; Enzyme Activation; Pyrimidines; 2',5'-Oligoadenylate Synthetase; RNA, Untranslated; Mutagenesis
• Research Categories: Chemistry, Biochemistry; Health Sciences, General

Abstract

Human 2'-5' oligoadenylate synthetase-1 (OAS1) is central in innate immune system detection of cytoplasmic double-stranded RNA (dsRNA) and promotion of host antiviral responses. However, the molecular signatures that promote OAS1 activation are currently poorly defined. We show that the 3'-end polyuridine sequence of viral and cellular RNA polymerase III non-coding transcripts is critical for their optimal activation of OAS1. Potentiation of OAS1 activity was also observed with a model dsRNA duplex containing an OAS1 activation consensus sequence. We determined that the effect is attributable to a single appended 3'-end residue, is dependent upon its single-stranded nature with strong preference for pyrimidine residues and is mediated by a highly conserved OAS1 residue adjacent to the dsRNA binding surface. These findings represent discovery of a novel signature for OAS1 activation, the 3'-single-stranded pyrimidine (3'-ssPy) motif, with potential functional implications for OAS1 activity in its antiviral and other anti-proliferative roles.