2-5A-Mediated decay (2-5AMD): from antiviral defense to control of host RNA

Abstract

Mammalian cells are exquisitely sensitive to the presence of double-stranded RNA (dsRNA), a molecule that they interpret as a signal of viral presence requiring immediate attention. Upon sensing dsRNA cells activate the innate immune response, which involves transcriptional mechanisms driving inflammation and secretion of interferons (IFNs) and interferon-stimulated genes (ISGs), as well as synthesis of RNA-like signaling molecules comprised of three or more 2′-5′-linked adenylates (2-5As). 2-5As were discovered some forty years ago and described as IFN-induced inhibitors of protein synthesis. The efforts of many laboratories, aimed at elucidating the molecular mechanism and function of these mysterious RNA-like signaling oligonucleotides, revealed that 2-5A is a specific ligand for the kinase-family endonuclease RNase L. RNase L decays single-stranded RNA (ssRNA) from viruses and mRNAs (as well as other RNAs) from hosts in a process we proposed to call 2-5A-mediated decay (2-5AMD). During recent years it has become increasingly recognized that 2-5AMD is more than a blunt tool of viral RNA destruction, but a pathway deeply integrated into sensing and regulation of endogenous RNAs. Here we present an overview of recently emerged roles of 2-5AMD in host RNA regulation.

Keywords:

• RNase L
• OAS3
• innate immunity
• endo-dsRNA
• RNA decay
• translation
• retroelements

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by NIH Grant 1R01GM110161-01 (to A.K.), Sidney Kimmel Foundation Grant AWD1004002 (to A.K.), Burroughs Wellcome Foundation Grant 1013579 (to A.K.), The Vallee Foundation (A.K.), National Institute of General Medical Services (NIGMS) Training Grant 5T32GM007388 (to E.P.), and National Heart, Lung, and Blood Institute (NHLBI) 1F31HL158123-01 (to E.P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.