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Prefoldin complex promotes interferon-stimulated gene expression and is inhibited by rotavirus VP3

Author

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  • Yinxing Zhu

    (Washington University School of Medicine)

  • Yanhua Song

    (Stanford School of Medicine
    Jiangsu Academy of Agricultural Sciences)

  • Dilip Kumar

    (Baylor College of Medicine
    Ashoka University)

  • Peter K. Jackson

    (Stanford School of Medicine)

  • B. V. Venkataram Prasad

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Siyuan Ding

    (Washington University School of Medicine)

Abstract

Timely induction of interferons and interferon-stimulated genes (ISGs) is critical for successful host defense against viral infections. VP3 encoded by rotavirus is implicated in interferon antagonism. However, the precise mechanisms remain incompletely understood. By conducting tandem-affinity purification coupled with high-resolution mass spectrometry, we identify the prefoldin complex as the top cellular binding partner of VP3. Rotavirus infection is significantly enhanced in prefoldin subunit knockout cells. Using proteome-wide label-free quantification, we find that prefoldin assists in folding ubiquitin-like-modifier-activating-enzyme-3 (UBA3), both of which positively regulate ISG expression. Through direct and competitive binding, VP3 interferes with the chaperone activity of prefoldin, leading to unstable UBA3, reduces IRF9, and suppresses ISG transcription. Our findings report a novel function of a prefoldin-UBA3-IRF9-ISG axis in antiviral immunity and uncover new aspects of virus-host interactions that could be exploited for broad-spectrum antiviral therapeutic development.

Suggested Citation

  • Yinxing Zhu & Yanhua Song & Dilip Kumar & Peter K. Jackson & B. V. Venkataram Prasad & Siyuan Ding, 2025. "Prefoldin complex promotes interferon-stimulated gene expression and is inhibited by rotavirus VP3," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63393-3
    DOI: 10.1038/s41467-025-63393-3
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