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

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.