Abstract
Infections by RNA viruses cause diseases. Host factor(s) that restrain viral propagation offer new anti-virus strategies. We use vesicular stomatitis virus (VSV) as a model and observe the synthesis of VSV RNAs at mitochondria/endoplasmic reticulum (Mito/ER) spheres, accompanied by the leakage of endonuclease G (ENDOG), a mitochondrial nuclease, to the cytosol. We provide evidence that ENDOG released from mitochondria is a host anti-viral factor by eliminating viral RNAs for replication. However, ENDOG outside mitochondria can translocate to nuclei and cause nuclear DNA damages. We engineer an ENDOG expressed on mitochondrial outer membrane (MOM), namely MOM-ENDOG, to increase the accessibility to viral RNA transcripts synthesized at mitochondrial sites without damaging nuclear DNA (nDNA). Delivery of modified mRNA of wild-type but not catalytic-dead MOM-ENDOG markedly suppresses not only the propagation of VSV, but also Dengue and Zika virus. Thus, this organelle-specific viral RNA degrader may be developed as a broad-spectrum anti-viral agent.
Acknowledgements
We thank the National RNAi Core Facility, Academia Sinica for ENDOG and LacZ shRNA plasmids. We thank the image core, the Biomedical Resource Core at the First Core Labs at College of Medicine National Taiwan University for the technical assistance. We thank Professor Chien-Kuo Lee and Li-Chung Hsu (National Taiwan University, Taiwan) for providing VSV and HIN1 virus.
Funding
C.-W.C. was supported by a grant from National Science and Technology Council, Taiwan (NSTC114-2811-B-002-107). W.-T.L. was supported by a grant from National Science and Technology Council, Taiwan (NSTC114-2811-B-002-090). T.C. was supported by a grant from Ministry of Education Higher Education SPROUT Project, Taiwan (113L4000-2).
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Chen, CW., Liao, WT., Chao, T. et al. An engineered viral RNA degrader on mitochondrial surface that mitigates RNA virus infection. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73487-1
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DOI: https://doi.org/10.1038/s41467-026-73487-1
