RNF213 isoform 2 restricts Zika virus through antiviral signaling and viral protein degradation

Several RING finger (RNF) family proteins exert antiviral effects primarily by regulating host antiviral pathways. Moreover, the longer isoform of RNF213 can also directly target viral proteins to inhibit infection. However, the antiviral potential of the shorter isoform of RNF213 (RNF213 isoform 2) remains unexplored. Here, we report that RNF213 isoform 2 (hereafter referred to as RNF213) activates the retinoic acid-inducible gene I (RIG-I)-melanoma differentiation-associated gene 5 (MDA5) pathway and promotes proteasomal and lysosomal degradation of multiple Zika virus (ZIKV) proteins, including the capsid (C), envelope (E), nonstructural 3 (NS3), and nonstructural 4B (NS4B) proteins, to restrict ZIKV infection. Notably, we identified a 23-amino acid peptide (PR-23) derived from RNF213 that degrades ZIKV proteins and suppresses viral replication in vitro . In conclusion, our findings not only elucidate a dual-targeting antiviral mechanism of RNF213 against ZIKV but also define a minimal functional domain of this isoform that mediates antiviral activity in vitro .