The human 2′-5′oligoadenylate synthetase family: Unique interferon-inducible enzymes catalyzing 2′-5′ instead of 3′-5′ phosphodiester bond formation

The demonstration by Kerr and colleagues that double-stranded (ds) RNA inhibits drastically protein synthesis in cell-free systems prepared from interferon-treated cells, suggested the existence of an interferon-induced enzyme, which is dependent on dsRNA. Consequently, two distinct dsRNA-dependent enzymes were discovered: a serine/threonine protein kinase that nowadays is referred to as PKR and a 2′-5′oligoadenylate synthetase (2′-5′OAS) that polymerizes ATP to 2′-5′-linked oligomers of adenosine with the general formula pppA(2′p5′A)n, n ≥ 1. The product is pppG2′p5′G when GTP is used as a substrate. Three distinct forms of 2′-5′OAS exist in human cells, small, medium, and large, which contain one, two, and three OAS units, respectively, and are encoded by distinct genes clustered on the 2′-5′OAS locus on human chromosome 12. OASL is an OAS like IFN-induced protein encoded by a gene located about 8 Mb telomeric from the 2′-5′OAS locus. OASL is composed of one OAS unit fused at its C-terminus with two ubiquitin-like repeats. The human OASL is devoid of the typical 2′-5′OAS catalytic activity. In addition to these structural differences between the various OAS proteins, the three forms of 2′-5′OAS are characterized by different subcellular locations and enzymatic parameters. These findings illustrate the apparent structural and functional complexity of the human 2′-5′OAS family, and suggest that these proteins may have distinct roles in the cell.