nsP3-FXR co-condensation enables alphavirus replication and reveals a targetable alphavirus vulnerability

  • Cell Rep. 2026 Jun 23;45(6):117495. doi: 10.1016/j.celrep.2026.117495.
Yifan Xie  1 ,  Jie Cao  1 ,  Xinya Yang  2 ,  Ruzhu Hou  3 ,  Suhong Qian  1 ,  Guojie Wang  4 ,  Shiyu Deng  1 ,  Luo-Na Lin  5 ,  Yue Liu  3 ,  Peiguo Yang  6 ,  Rong Zhang  4 ,  Qiang Ding  7 ,  Peng Sun  2 ,  Wenchun Fan  8
Affiliations
  • 1. Life Sciences Institute, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, Zhejiang, China; Department of Infectious Diseases, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou 310052, Zhejiang, China.
  • 2. School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo, Zhejiang, China.
  • 3. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases of the First Affiliated Hospital and Department of Microbiology, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
  • 4. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 5. Department of Infectious Diseases, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou 310052, Zhejiang, China.
  • 6. Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
  • 7. Center for Infection Biology, School of Basic Medical Sciences, Tsinghua University, Beijing, China.
  • 8. Life Sciences Institute, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, Zhejiang, China; Department of Infectious Diseases, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou 310052, Zhejiang, China. Electronic address: [email protected].
PMID: 42241276 DOI: 10.1016/j.celrep.2026.117495
Abstract

Alphaviruses are mosquito-borne RNA viruses that pose a significant threat to humans, with risks worsened by global warming. Non-structural protein 3 (nsP3) is critical for alphavirus Infection, yet its precise roles remain poorly defined. Using Venezuelan equine encephalitis virus (VEEV) as a model, this study reveals that alphavirus unique domain (AUD) of nsP3 is essential for its condensation and viral replication. nsP3 forms gel-like condensates to bind to the second Tudor domain of Fragile X-related protein 1 (FXR1), forming replication supporting complexes. FXR1 bridges nsP3 and viral RNA within these condensates, which compartmentalize viral replication independent of protein interactions. Furthermore, UBAP2L was identified as a condensate-resident restriction factor against VEEV. Based on conserved AUD across alphaviruses, we developed a "21 R-AUD" Antiviral strategy by fusing TRIM21's RING domain to VEEV's AUD. This approach induces proteasomal degradation of nsP3 condensates and inhibits replication of multiple alphaviruses, establishing conserved nsP3 condensation as a broad-spectrum Antiviral target.

Keywords
CP: microbiology; RING-bait technology; alphaviruses; antiviral strategy; biomolecular condensation; fragile X-related 1; non-structural protein 3.
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