An Engineered Viral RNA Degrader on Mitochondrial Surface that Mitigates RNA Virus Infection [E vs ECD]

Infections by RNA viruses cause diseases. Host factor(s) that restrain viral propagation might offer opportunities for designing new anti-virus treatments. We used vesicular stomatitis virus (VSV) as a study model, and observed 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 be translocated to nuclei to cause nuclear DNA damages. We engineered 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 suppressed not only the propagation of VSV, but also Dengue, and Zika virus. Thus, this organelle-specific viral RNA degrader might be developed as a broad-spectrum anti-viral agent.