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

Cell Death & Differentiation (2024)Cite this article

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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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Fig. 1: ASB3 expression induced by IAV infection.
Fig. 2: ASB3 negatively regulates type I IFN production.
Fig. 3: ASB3 deficiency enhances the type I IFN response.
Fig. 4: ASB3 specifically interacts with MAVS.
Fig. 5: ASB3 potentiates K48-linked polyubiquitination and degradation of MAVS.
Fig. 6: ASB3-mediated MAVS degradation at residue K297.
Fig. 7: Loss of ASB3 enhances in vivo antiviral immunity.
Fig. 8: ASB3 deficiency eliminates MAVS degradation in the lungs.
Fig. 9: A working model of ASB3 inhibition of antiviral immunity.

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Full and uncropped western blots can be found in Supplementary Materials. All datasets analyzed in the study are available from the corresponding authors upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (32202890, 32273043, U21A20261), the Science and Technology Development Program of Changchun City (21ZY42), and the China Agriculture Research System of MOF and MARA (CARS-35).

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Author notes

  1. These authors contributed equally: Mingyang Cheng, Yiyuan Lu, Xin Cao.

Authors and Affiliations

  1. College of Veterinary Medicine, Jilin Agricultural University, Changchun, China

    Mingyang Cheng, Yiyuan Lu, Jiarui Wang, Haixu Wang, Yu Sun, Wenhui Zhao, Junhong Wang, Chunwei Shi, Jiawei Luo, Ming Gao, Tianxin Yu, Jianzhong Wang, Jiayao Guan, Nan Wang, Wentao Yang, Yanlong Jiang, Haibin Huang, Guilian Yang, Xin Cao, Chunfeng Wang & Yan Zeng

  2. Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China

    Mingyang Cheng, Yiyuan Lu, Jiarui Wang, Haixu Wang, Yu Sun, Wenhui Zhao, Junhong Wang, Chunwei Shi, Jiawei Luo, Ming Gao, Tianxin Yu, Jianzhong Wang, Jiayao Guan, Nan Wang, Wentao Yang, Yanlong Jiang, Haibin Huang, Guilian Yang, Xin Cao, Chunfeng Wang & Yan Zeng

  3. Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China

    Mingyang Cheng, Yiyuan Lu, Jiarui Wang, Haixu Wang, Yu Sun, Wenhui Zhao, Junhong Wang, Chunwei Shi, Jiawei Luo, Ming Gao, Tianxin Yu, Jianzhong Wang, Jiayao Guan, Nan Wang, Wentao Yang, Yanlong Jiang, Haibin Huang, Guilian Yang, Xin Cao, Chunfeng Wang & Yan Zeng

  4. Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China

    Mingyang Cheng, Yiyuan Lu, Jiarui Wang, Haixu Wang, Yu Sun, Wenhui Zhao, Junhong Wang, Chunwei Shi, Jiawei Luo, Ming Gao, Tianxin Yu, Jianzhong Wang, Jiayao Guan, Nan Wang, Wentao Yang, Yanlong Jiang, Haibin Huang, Guilian Yang, Xin Cao, Chunfeng Wang & Yan Zeng

  5. Department of Laboratory Medicine of Huashan Hospital, Fudan University, Shanghai, China

    Dongqin Yang

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  1. Mingyang Cheng
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Contributions

MC performed the majority of the experiments. YS, JW, YL, CS, RW, XW, JL, and WZ contributed to and/or supported us in some experiments. XC, YZ, and MC contributed to the animal studies and wrote the manuscript. JW, NW, WY, YJ, MG, TY, JG, and HH participated in the inflammation evaluation experiments. MC and YL analyzed and interpreted the data. MC, YZ, GY, CW, and XC conceived and designed the experiments, interpreted the data, and wrote the manuscript. YZ acts as a guarantor for the present study. All the authors discussed the results and approved the final manuscript.

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Correspondence to Xin Cao, Dongqin Yang, Chunfeng Wang or Yan Zeng.

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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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Cheng, M., Lu, Y., Wang, J. et al. The E3 ligase ASB3 downregulates antiviral innate immunity by targeting MAVS for ubiquitin-proteasomal degradation. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01376-5

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