Alternative splicing broadens antiviral diversity at the human OAS2 locus

Interferons (IFN) are cytokines that regulate the expression of hundreds of genes during viral infections to generate a broadly antiviral environment in the stimulated cell. Antiviral breadth is provided by the concurrent expression of many individual IFN-stimulated genes (ISG), each encoding a protein with often exquisite antiviral specificity. Here, we identify mechanistic plasticity at a single genetic locus as a novel mechanism to diversify the antiviral profile of human cells. Through alternative splicing, the OAS2 gene encodes two antiviral molecules with distinct target specificities. The shorter OAS2 p69 isoform restricts seasonal human coronavirus OC43 (HCoV-OC43), whereas the longer p71 isoform restricts picornavirus Cardiovirus A (EMCV). The restriction profile is determined by the variable length OAS2 C-terminal tails. Notably, these antiviral activities differ in their dependence on RNase L, suggesting that alternative splicing separates canonical restriction and virus sensing functions across two distinct OAS2 polypeptides. Together, these findings show how alternative splicing expands antiviral diversity at the human OAS2 locus.