OAS cross-activates RNase L intercellularly through cell-to-cell transfer of 2-5A to spread innate immunity

The 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway is a classical antiviral innate immune pathway. Upon sensing dsRNA, OAS produces 2',5'-oligoadenylate (2-5A) as a second messenger to activate RNase L. Whether 2-5A can be transported to extend the reach of innate immune signaling has not been established. Here, we showed that 2-5A was transferred from cell to cell through connexin (CX43/CX45) gap junctions. 2-5A was also transferred through importers and exporters, allowing OAS to remotely activate RNase L and protect neighboring cells from viral infection. We identified ABCC10 as a 2-5A exporter. Loss of ABCC10 had no effect on 2-5A production but reduced 2-5A export and protection of neighboring cells. Furthermore, OAS(hi) tumors such as MC38 naturally produced 2-5A in vivo, which was secreted via ABCC10 to activate host-not tumor-RNase L-mediated antitumor response. Therefore, 2-5A is an immunotransmitter that mediates short-range communication between cells in infection and cancer.