OAS-gene family

In humans, the OAS gene family consists of four genes:

• OAS1
• OAS2
• OAS3 and the
• OAS like protein - OASL.

OASL does not possess 2'5' OAS activity (Rebouillat D et al. 1999). The OAS1, OAS2 and OAS3 genes are encoded by a tightly coupled locus on 12q24.1. The additional member of the human OAS family is the OASL gene, which is localized to 12q24.2. Alternative splicing increases the number of distinct isoforms to 11:

• OAS1 encodes five isoforms at oligoadenylate synthetases (p42, p44, p46, p48 and p52).
• OAS2 encodes 2 OAS isoforms (p69 and p71)
• OAS3 mRNA is spliced in only one way and leads to the expression of the protein p100
• OASL encodes three OAS isoforms (p30, p45 and p59) (Rebouillat D et al. 1998)

Each OAS gene consists of a conserved OAS unit composed of five translated exons (exons A-E). Synthesis of the various oligoadenylate synthetases is induced in response to viral infection by type I IFN via IRF1 (Behera AK et al 2002). Gene activation occurs through the binding of dsRNA (142) or hairpin structures such as HIV-1 TAR RNA. This leads to oligomerization of the OAS or formation of 2-5 A dimers (OAS3) (170). This now active OAS is capable of polymerizing ATP. The result is 2-5 A oligomers (OAS1 and OAS2) or 2-5 A dimers (OAS3) (Rebouillat D et al. 1999).

In order to activate RNase L, the 2-5A must consist of a scaffold of at least three adenylyl residues and carry a 5' monophosphate or 5' triphosphate, which provides different targets for the cellular antagonists of the 2'5' OAS. Since in the absence of a 5' phosphoryl group, RNase L activity is reduced more than 100-fold (Dong B et al. 1994), inhibition via 2-5 A dephosphorylation is possible. In addition, 2-5 A is degraded by a cellular 2' phosphodiesterase (2'-PDE) and the 2' 5' oligoadenylate synthetase / RNase L system is inhibited in this manner (Kubota K, et al. 2004). The effector protein of this antiviral system is RNase L ( L = latent). This is a ubiquitinously expressed enzyme in mammalian cells with a length of 741 AS and a molecular weight of 83.5 kDa. RNase L requires 2-5 A for its activation and can be located either in the cytoplasm or in the nucleus, depending on the cell cycle. In the inactive form, the enzyme is present in a closed conformation as a monomer. Upon binding of 2-5 A to the N-terminal ankyrin repeats 2 and 4, the RNase transitions to an open conformation, assembles into an active homodimer, and the C-terminal catalytic domain becomes accessible. To prevent excessive activation of RNase L, RNase L inhibitor (RLI) binds to RNase, preventing interaction with activating 2-5 A (Bisbal C et al. 1995).

RNase L cleaves RNA exclusively in single-stranded regions preferentially at the 3' end of a UU or UA sequence. However, interfaces are also less likely to occur downstream of other sequences. The resulting sequencing products carry a 5' OH group and a 3' monophosphate .

2',5'-Oligoadenylate synthetases (2',5'-OAS) were discovered and characterized as interferon (IFN)-induced enzymes that convert ATP to 2',5'-linked oligomers of adenosine in the presence of double-stranded (ds) RNA.

1. Behera AK et al. (2002) 2'-5' oligoadenylate synthetase plays a critical role in interferon-gamma inhibition of respiratory syncytial virus infection of human epithelial cells. The Journal of biological chemistry 277:25601-25608.
2. Bisbal C et al. (1995) Cloning and characterization of a RNAse L inhibitor. A new component of the interferonregulated 2-5A pathway. J Biol Chem 270:13308-13317
3. Dong B, et al. (1994) Intrinsic molecular activities of the interferon-induced 2- 5A-dependent RNase. J Biol Chem 269:14153-14158.
4. Kubota K et al (2004) Identification of 2'-phosphodiesterase, which plays a role in the 2-5A system regulated by interferon. J Biol Chem 279:37832-37841.
5. KWON YC et al. (2013) The ribonuclease Ldependent antiviral roles of human 2',5'-oligoadenylate synthetase family members against hepatitis C virus. FEBS Lett 587: 156-164
6. Rebouillat D et al (1999) The human 2',5'-oligoadenylate synthetase family: interferon-induced proteins with unique enzymatic properties. J Interferon Cytokine Res 19:295-308.
7. Rebouillat D et al. (1998) Molecular cloning and characterization of two related and interferon-induced 56-kDa and 30-kDa proteins highly similar to 2'-5' oligoadenylate synthetase. European journal of biochemistry / FEBS 257:319-330.