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

  • iScience. 2026 Jun 5;29(6):116284. doi: 10.1016/j.isci.2026.116284.
Xiaoyu Yang  1 ,  Teng Chen  2  3 ,  Bin Ren  4 ,  Jinqiu Liu  3 ,  Zhen Xu  5 ,  Jingyi Wang  5 ,  Yiran Shi  5 ,  Lihua Liu  6 ,  Lili Li  7 ,  Genhong Cheng  7 ,  Dongming Zhou  1 ,  Qi Chen  3 ,  Shulong Zu  5
Affiliations
  • 1. Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 2. Key Laboratory of Jilin Province for Zoonoses Prevention and Control, State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Changchun 130122, China.
  • 3. State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China.
  • 4. Senior Department of Neurosurgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
  • 5. Department of Toxicology and Health Inspection and Quarantine, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
  • 6. School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China.
  • 7. Guangzhou National Laboratory, Guangzhou 510005, China.
PMID: 42305619 DOI: 10.1016/j.isci.2026.116284
Abstract

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.

Keywords
biochemistry; virology.
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