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

  • Immunity. 2025 Apr 8;58(4):797-810.e6. doi: 10.1016/j.immuni.2025.01.016.
Wanwan Huai  1 ,  Kun Yang  1 ,  Cong Xing  1 ,  Kun Song  1 ,  Heng Lyu  1 ,  Noelle S Williams  2 ,  Jianjun Wu  3 ,  Nan Yan  4
Affiliations
  • 1. Department of Immunology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3. Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: [email protected].
  • 4. Department of Immunology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 40010341 DOI: 10.1016/j.immuni.2025.01.016
Abstract

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, OAShi 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.

Keywords
2-5A; ABCC10; OAS; RNase L; antitumor immunity; gap junction; immunotransmitter; type I interferon.
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