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RNF138-Mediated Ubiquitination and Degradation of NS5 Restricts Tick-Borne Encephalitis Virus Infection
Jialiang Sun1, Weijing Yang1, Hao Zhou1
1Institute of Virology and AIDS Research, Centre of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, the First Hospital of Jilin University, Changchun, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 10, 2026
Summary
The E3 ubiquitin ligase RNF138 restricts tick-borne encephalitis virus (TBEV) by degrading its NS5 protein. This host defense mechanism reduces viral replication and improves survival in mice.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Tick-borne encephalitis virus (TBEV) causes severe neurological disease.
- Host restriction mechanisms against TBEV replication are not fully understood.
Purpose of the Study:
- Identify host factors restricting TBEV replication.
- Elucidate the molecular mechanisms of host antiviral defense against TBEV.
Main Methods:
- Identified RNF138 as a restriction factor targeting TBEV NS5.
- Investigated RNF138-NS5 interaction and NS5 ubiquitination.
- Assessed the impact of RNF138 on TBEV and Zika virus replication in vitro and in vivo.
- Analyzed the conservation of RNF138 antiviral activity.
Main Results:
- RNF138 directly binds TBEV NS5 via its ubiquitin-interacting motif.
- RNF138 catalyzes K48-linked polyubiquitination of NS5, leading to its degradation.
- RNF138 suppresses TBEV and Zika virus replication by degrading NS5.
- RNF138 expression reduces viral load, neuroinflammation, and mortality in TBEV-infected mice.
- Antiviral activity of RNF138 is conserved in mammals but absent in arthropods.
Conclusions:
- RNF138-mediated degradation of NS5 is a key intrinsic defense against TBEV.
- This mechanism highlights host-specific antiviral adaptation against flaviviruses.
- Targeting viral replicases for degradation offers a therapeutic strategy.
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