The Many Faces of Oligoadenylate Synthetases

Abstract

2'-5' Oligoadenylate synthetases (OAS) are interferon-stimulated genes that are most well-known to protect hosts from viral infections. They are evolutionarily related to an ancient family of Nucleotidyltransferases, which are primarily involved in pathogen-sensing and innate immune response. Classical function of OAS proteins involves double-stranded RNA-stimulated polymerization of adenosine triphosphate in 2'-5' oligoadenylates (2-5A), which can activate the latent RNase (RNase L) to degrade RNA. However, accumulated evidence over the years have suggested alternative mode of antiviral function of several OAS family proteins. Furthermore, recent studies have connected some OAS proteins with wider function beyond viral infection. Here, we review some of the canonical and noncanonical functions of OAS proteins and their mechanisms.

Keywords: West Nile virus; antiviral mechanism; interferon; interferon-stimulated genes; oligoadenylate synthetase.

FIG. 1.

Human and mouse OAS genes and protein isoforms. OAS loci of human chromosome 12 and mouse chromosome 5 are shown with enzymatically active (green) and inactive (red) OAS genes. Enzymatically functional (green), enzymatically nonfunctional (red) OAS protein domains are shown below with UBL (orange) domains in OASL proteins. Known functions with published (solid lines) and unpublished (dotted lines) mechanisms are shown in the context of specific virus infection. EMCV, Encephalomyocarditis virus; HSV, Herpes simplex virus; OAS, 2′–5′ Oligoadenylate Synthetases; OASL, OAS-like; SeV, Sendai virus; VSV, vesicular stomatitis virus; VV, Vaccinia virus; SARS-CoV-2, SARS coronavirus 2; UBL, ubiquitin-like; WNV, West Nile virus.

FIG. 2.

Involvement of human OAS1 and mouse Oas1b in protection from WNV. Schematic representation of human OAS1 gene (green), the location of SNP rs10774671 and the exons coding for P46 and P42 (top left); and mouse Oas1b gene (red) and the location of the STOP (*) codon in C57BL6 is on the top right. Outcome of WNV infection in both cases are indicated as—resistant (green) sensitive (red). Protein sequence alignment of P42 and P46 C terminal region with highlighted CaaX motif is shown in the middle. Differential cellular localization of P42 and P46. OAS1-deficient HT1080 cells restored with inducible P42 or P46 expression were treated with Doxycycline, stained with OAS1 antibody, and imaged on a confocal microscope as shown in lower left. Genotypes of SNP rs10774671 and rs1131454 of several commonly used cell lines are shown in the lower right-hand corner. SNP, single nucleotide polymorphism.

FIG. 3.

Effect of various human OAS deficiency on intracellular bacterial replication. Indicated OAS-deficient THP1 cells were infected with either Francisella novicida or Listeria monocytogenes as indicated followed by quantitation of bacterial burden using colony-forming assay. MOI, multiplicity of infection.