Zee-Fen Chang

Chair Professor, Institute of Molecular Medicine, Director, Center of Nucleic Acid Medicines at College of Medicine, National Taiwan University

Speaker

The high frequency of RNA virus mutations and the outbreak of emergent RNA viral infection remain the challenging issues in public health. We 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 the propagation of VSV, Influenza, Dengue and Zika virus. Thus, the mRNA encoding organelle-specific viral RNA degrader can be developed to a broad-spectrum anti-viral agent.