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

Qiu Pan, Yan Xie, Ying Zhang, Xinqi Guo, Jing Wang, Min Liu () and Xiao-Lian Zhang ()
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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)

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44960-6

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