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EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses

Author

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  • Qiu Pan

    (Wuhan University TaiKang Medical School (School of Basic Medical Sciences))

  • Yan Xie

    (Wuhan University TaiKang Medical School (School of Basic Medical Sciences))

  • Ying Zhang

    (Wuhan University TaiKang Medical School (School of Basic Medical Sciences))

  • Xinqi Guo

    (Wuhan University TaiKang Medical School (School of Basic Medical Sciences))

  • Jing Wang

    (Wuhan University TaiKang Medical School (School of Basic Medical Sciences))

  • Min Liu

    (Wuhan University TaiKang Medical School (School of Basic Medical Sciences))

  • Xiao-Lian Zhang

    (Wuhan University TaiKang Medical School (School of Basic Medical Sciences)
    Wuhan University)

Abstract

Aberrant N-glycosylation has been implicated in viral diseases. Alpha-(1,6)-fucosyltransferase (FUT8) is the sole enzyme responsible for core fucosylation of N-glycans during glycoprotein biosynthesis. Here we find that multiple viral envelope proteins, including Hepatitis C Virus (HCV)-E2, Vesicular stomatitis virus (VSV)-G, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-Spike and human immunodeficiency virus (HIV)-gp120, enhance FUT8 expression and core fucosylation. HCV-E2 manipulates host transcription factor SNAIL to induce FUT8 expression through EGFR-AKT-SNAIL activation. The aberrant increased-FUT8 expression promotes TRIM40-mediated RIG-I K48-ubiquitination and suppresses the antiviral interferon (IFN)-I response through core fucosylated-EGFR-JAK1-STAT3-RIG-I signaling. FUT8 inhibitor 2FF, N-glycosylation site-specific mutation (Q352AT) of EGFR, and tissue-targeted Fut8 silencing significantly increase antiviral IFN-I responses and suppress RNA viral replication, suggesting that core fucosylation mediated by FUT8 is critical for antiviral innate immunity. These findings reveal an immune evasion mechanism in which virus-induced FUT8 suppresses endogenous RIG-I-mediated antiviral defenses by enhancing core fucosylated EGFR-mediated activation.

Suggested Citation

  • Qiu Pan & Yan Xie & Ying Zhang & Xinqi Guo & Jing Wang & Min Liu & Xiao-Lian Zhang, 2024. "EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44960-6
    DOI: 10.1038/s41467-024-44960-6
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    References listed on IDEAS

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    1. Brett D. Lindenbach & Charles M. Rice, 2005. "Unravelling hepatitis C virus replication from genome to function," Nature, Nature, vol. 436(7053), pages 933-938, August.
    2. Xin Wang & Shu-Mei Huong & Marie L. Chiu & Nancy Raab-Traub & Eng-Shang Huang, 2003. "Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus," Nature, Nature, vol. 424(6947), pages 456-461, July.
    3. Line S. Reinert & Katarína Lopušná & Henriette Winther & Chenglong Sun & Martin K. Thomsen & Ramya Nandakumar & Trine H. Mogensen & Morten Meyer & Christian Vægter & Jens R. Nyengaard & Katherine A. F, 2016. "Sensing of HSV-1 by the cGAS–STING pathway in microglia orchestrates antiviral defence in the CNS," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
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