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. 2024 Dec;31(12):1746-1760.
doi: 10.1038/s41418-024-01376-5. Epub 2024 Sep 12.

The E3 ligase ASB3 downregulates antiviral innate immunity by targeting MAVS for ubiquitin-proteasomal degradation

Mingyang Cheng #  1   2   3   4 , Yiyuan Lu #  1   2   3   4 , Jiarui Wang  1   2   3   4 , Haixu Wang  1   2   3   4 , Yu Sun  1   2   3   4 , Wenhui Zhao  1   2   3   4 , Junhong Wang  1   2   3   4 , Chunwei Shi  1   2   3   4 , Jiawei Luo  1   2   3   4 , Ming Gao  1   2   3   4 , Tianxin Yu  1   2   3   4 , Jianzhong Wang  1   2   3   4 , Jiayao Guan  1   2   3   4 , Nan Wang  1   2   3   4 , Wentao Yang  1   2   3   4 , Yanlong Jiang  1   2   3   4 , Haibin Huang  1   2   3   4 , Guilian Yang  1   2   3   4 , Xin Cao #  5   6   7   8 , Dongqin Yang  9 , Chunfeng Wang  10   11   12   13 , Yan Zeng  14   15   16   17
Affiliations

The E3 ligase ASB3 downregulates antiviral innate immunity by targeting MAVS for ubiquitin-proteasomal degradation

Mingyang Cheng et al. Cell Death Differ. 2024 Dec.

Abstract

E3 ubiquitin ligases are very important for regulating antiviral immunity during viral infection. Here, we discovered that Ankyrin repeat and SOCS box-containing protein 3 (ASB3), an E3 ligase, are upregulated in the presence of RNA viruses, particularly influenza A virus (IAV). Notably, overexpression of ASB3 inhibits type I IFN (IFN-I) responses induced by Sendai virus (SeV) and IAV, and ablation of ASB3 restores SeV and H9N2 infection-mediated transcription of IFN-β and its downstream interferon-stimulated genes (ISGs). Interestingly, animals lacking ASB3 presented decreased susceptibility to H9N2 and H1N1 infections. Mechanistically, ASB3 interacts with MAVS and directly mediates K48-linked polyubiquitination and degradation of MAVS at K297, thereby inhibiting the phosphorylation of TBK1 and IRF3 and downregulating downstream antiviral signaling. These findings establish ASB3 as a critical negative regulator that controls the activation of antiviral signaling and describe a novel function of ASB3 that has not been previously reported.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics: All animal procedures were performed in accordance with the Guide for Care and Use of Laboratory Animals of Jilin Agricultural University and were approved by the Animal Ethics Committee of Jilin Agricultural University.

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