Lumpy skin disease virus ORF127 protein suppresses type I interferon responses by inhibiting K63-linked ubiquitination of tank binding kinase 1

文献类型： 外文期刊

第一作者： Liang, Zhengji

作者： Liang, Zhengji;Wang, Shasha;Yao, Kaishen;Ren, Shanhui;Cheng, Pengyuan;Qu, Min;Ma, Xiaoqin;Gao, Xin;Yin, Xiangping;Wang, Xiangwei;Sun, Yuefeng

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关键词： IFN-beta; immune evasion; lumpy skin disease virus; ORF127; TBK1

期刊名称：FASEB JOURNAL （ 影响因子：4.8； 五年影响因子：5.2 ）

ISSN： 0892-6638

年卷期： 2024 年 38 卷 3 期

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收录情况： SCI

摘要： Lumpy skin disease (LSD) is a severe animal infectious disease caused by lumpy skin disease virus (LSDV), inducing extensive nodules on the cattle mucosa or the scarfskin. LSDV genome encodes multiple proteins to evade host innate immune response. However, the underlying molecular mechanisms are poorly understood. In this study, we found that LSDV could suppress the expression of IFN-beta and interferon-stimulated genes (ISGs) in MDBK cells during the early stage of infection. Subsequently, an unbiased screen was performed to screen the LSDV genes with inhibitory effects on the type I interferon (IFN-I) production. ORF127 protein was identified as one of the strongest inhibitory effectors on the expression of IFN-beta and ISGs, meanwhile, the 1-43 aa of N-terminal of ORF127 played a vital role in suppressing the expression of IFN-beta. Overexpression of ORF127 could significantly promote LSDV replication through inhibiting the production of IFN-beta and ISGs in MDBK cells. Mechanism study showed that ORF127 specifically interacted with TBK1 and decreased the K63-linked polyubiquitination of TBK1 which suppressed the phosphorylation of TBK1 and ultimately decreased the production of IFN-beta. In addition, truncation mutation analysis indicated that the 1-43 aa of N-terminal of ORF127 protein was the key structural domain for its interaction with TBK1. In short, these results validated that ORF127 played a negative role in regulating IFN-beta expression through cGAS-STING signaling pathway. Taken together, this study clarified the molecular mechanism of ORF127 gene antagonizing IFN-I-mediated antiviral, which will helpfully provide new strategies for the treatment and prevention of LSD.

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