RNA regulation of the antiviral protein 2′‐5′‐oligoadenylate synthetase

Abstract

The innate immune system is a broad collection of critical intra‐ and extra‐cellular processes that limit the infectivity of diverse pathogens. The 2′‐5′‐oligoadenylate synthetase (OAS) family of enzymes are important sensors of cytosolic double‐stranded RNA (dsRNA) that play a critical role in limiting viral infection by activating the latent ribonuclease (RNase L) to halt viral replication and establish an antiviral state. Attesting to the importance of the OAS/RNase L pathway, diverse viruses have developed numerous distinct strategies to evade the effects of OAS activation. How OAS proteins are regulated by viral or cellular RNAs is not fully understood but several recent studies have provided important new insights into the molecular mechanisms of OAS activation by dsRNA. Other studies have revealed unanticipated features of RNA sequence and structure that strongly enhance activation of at least one OAS family member. While these discoveries represent important advances, they also underscore the fact that much remains to be learned about RNA‐mediated regulation of the OAS/RNase L pathway. In particular, defining the full complement of RNA molecular signatures that activate OAS is essential to our understanding of how these proteins maximize their protective role against pathogens while still accurately discriminating host molecules to avoid inadvertent activation by cellular RNAs. A more complete knowledge of OAS regulation may also serve as a foundation for the development of novel antiviral therapeutic strategies and lead the way to a deeper understanding of currently unappreciated cellular functions of the OAS/RNase L pathway in the absence of infection. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Translation > Translation Regulation

Innate Immune DNA Sensing of Flaviviruses

“…The list for the currently known innate immune PRRs is extensive and has been steadily expanding in the past three decades since the discovery of the first Toll-like receptors (TLRs) by Hoffmann in 1996 after Janeway's earlier prediction [18]. Now, the field has advanced tremendously beyond the TLR family, adding new sensors like the nucleotide-binding oligomerization domain-like receptor (NLR) family and its subfamilies (such as NLRP), RIG-I-like receptor (RLR) family, 2 -5 oligoadenylate synthase (OAS) family, DEAD box polypeptide 41 (DDX41), stimulator of interferon genes (STING), cyclic GAMP synthase (cGAS), IFN-γ-inducible protein 16 (IFI16), and others to the long roster of molecular sentinels watching the host cellular space [19][20][21][22][23][24][25][26]. These receptors and their respective signaling pathways have been actively studied and described based on the pathogen components that they detect (foreign lipids, proteins, or nucleic acid structures or sequences) along with their proposed cellular localizations [27,28].…”

Human OAS1 activation is highly dependent on both RNA sequence and context of activating RNA motifs

“…Double-stranded RNA (dsRNA) is often a hallmark of viral infection, present in viral genomes or produced as a consequence of viral gene expression or replication ( 3–5 ). dsRNA is thus a potent PAMP detected by several distinct human cellular pattern recognition receptors, including the 2′-5′-oligoadenylate synthetase (OAS) family of cytosolic dsRNA sensors which restrict replication of multiple viruses ( 6 , 7 ).…”

Synthesis, Structure, and Function of Human Adenovirus Small Non-Coding RNAs

“…Another well-known dsRNA sensor, able to recognize virus infections and induces an anti-viral response in virus-infected cells, is 2’-5’ Oligoadenylate Synthetase (OAS) [ 66 ]. In the presence of dsRNA, the OAS enzyme polymerizes ATP into a 2’-5’-oligoadenylate, which activates the latent form of ribonuclease L (RNaseL).…”

“…The active form of RNaseL in turn degrades both cellular and viral RNA thereby inhibiting virus growth [ 67 ]. The human genome encodes a family of three catalytically active OAS enzymes (OAS1, OAS2, and OAS3), which have different sensitivities to dsRNA dependent on its length and sequence [ 66 ]. Since the OAS proteins show anti-viral activities, many viruses encode antagonists against the OAS proteins [ 66 ].…”