EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses
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,...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-44960-6 |
| _version_ | 1797276381402365952 |
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| author | Qiu Pan Yan Xie Ying Zhang Xinqi Guo Jing Wang Min Liu Xiao-Lian Zhang |
| author_facet | Qiu Pan Yan Xie Ying Zhang Xinqi Guo Jing Wang Min Liu Xiao-Lian Zhang |
| author_sort | Qiu Pan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T15:28:27Z |
| format | Article |
| id | doaj.art-1be423cfc75549c18a59b43f02e096bf |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T15:28:27Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-1be423cfc75549c18a59b43f02e096bf2024-03-05T16:35:05ZengNature PortfolioNature Communications2041-17232024-01-0115111910.1038/s41467-024-44960-6EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defensesQiu Pan0Yan Xie1Ying Zhang2Xinqi Guo3Jing Wang4Min Liu5Xiao-Lian Zhang6State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences)State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences)State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences)State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences)State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences)State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences)State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences)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.https://doi.org/10.1038/s41467-024-44960-6 |
| spellingShingle | Qiu Pan Yan Xie Ying Zhang Xinqi Guo Jing Wang Min Liu Xiao-Lian Zhang EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses Nature Communications |
| title | EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses |
| title_full | EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses |
| title_fullStr | EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses |
| title_full_unstemmed | EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses |
| title_short | EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses |
| title_sort | egfr core fucosylation induced by hepatitis c virus promotes trim40 mediated rig i ubiquitination and suppresses interferon i antiviral defenses |
| url | https://doi.org/10.1038/s41467-024-44960-6 |
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