A human cellular noncoding RNA activates the antiviral protein 2 '-5 '-oligoadenylate synthetase 1

• Type of Material: Article
• Authors: Brenda M. Calderon, Emory University; Graeme L Conn, Emory University
• Language: English
• Date: 2018-10-12
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Calderon and Conn.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.RA118.004747
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 293
• Issue: 41
• Start Page: 16115
• End Page: 16124
• Grant/Funding Information: This work was supported by an award from the Emory University Research Council (URC) (to G. L. C.), a scholarship from the ARCS Foundation (to B. M. C.), and by BCDB NIGMS Training Grant T32-GM008367 from the National Institutes of Health.
• Keywords: KINASE PKR; INFECTION; Biochemistry & Molecular Biology; Life Sciences & Biomedicine; TRANSLATION; HUMAN OLIGOADENYLATE SYNTHETASE; REVEALS; REGULATORS; DSRNA; INHIBITION; Science & Technology; ROLES; PKR ACTIVATION
• Research Categories: Chemistry, Biochemistry; Biology, Cell

Abstract

The 2–5-oligoadenylate synthetase (OAS) family of enzymes sense cytosolic dsRNA, a potent signal of viral infection. In response to dsRNA binding, OAS proteins synthesize the second messenger 2–5-linked oligoadenylate that activates the latent ribonuclease L (RNase L). RNase L–mediated degradation of viral and cellular RNAs effectively halts viral replication and further stimulates innate immune responses by inducing type I interferon. The OAS/RNase L pathway is therefore central in innate immune recognition and promotion of antiviral host responses. However, the potential for specific RNA sequences or structures to drive OAS1 activation and the molecular mechanisms by which they act are not currently fully understood. Moreover, the cellular regulators of OAS activity are not well defined. Here, we demonstrate that the human cellular noncoding RNA 886 (nc886) activates OAS1 both in vitro and in human A549 cells. We show that a unique structure present only in one of the two structural conformers adopted by nc886 drives potent OAS1 activation. In contrast, the conformer lacking this unique structure activated OAS1 only very weakly. We also found that formation of this OAS1-activating structural motif depends on the nucleotides in the apical-most loop of nc886 and the adjacent helix. These findings identify a cellular RNA capable of activating the OAS/RNase L pathway in human cells and illustrate the importance of structural elements, and their context, in potentiating OAS1 activity.