The double-stranded RNA (dsRNA) sensor 2′,5′-oligoadenylate synthetase (OAS) produces the linear oligonucleotide 2-5A, which binds to and activates RNase L to cleave host and viral RNA and activate RIG-I-like receptors. In Immunity, Yan and colleagues show that 2-5A is transferred from cell to cell through gap junctions to mediate short-range communication between cells during infection and cancer. RNase L-knockout A549 cells treated with poly(I:C) activate RNA cleavage in OAS-knockout A549 cells, whereas A549 cells expressing a constitutively active OAS induce IFN and ISG expression in wild-type but not in RNase L-knockdown mouse embryonic fibroblasts, both in a manner dependent on the connexins CX43 and CX45, which form gap junctions. Most cell types produce 2-5A after treatment with IFN or poly(I:C) and some also export it to the extracellular space. Extracellular 2-5A is imported in cells through the same transporters as the cyclic dinucleotide cGAMP. In culture, cells that can produce, export and import 2-5A have better control of VSV viral infection. In a model of MC38 cells implanted subcutaneously into C56BL/6 mice, MC38 cells that cannot make or export 2-5A or MC38 cells implanted in Rnasel−/−, Rag1−/− or Ifnar1−/− mice grow faster than their wild-type counterparts. Expression of OAS correlates positively with the level of CD8+ T cell infiltration and better survival in human cancer.

Original reference: Immunity 58, 797–810 (2025)