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

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; Dongqin Yang; Chunfeng Wang; Yan Zeng

doi:10.1038/s41418-024-01376-5

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

Cell Death Differ. 2024 Sep 12. doi: 10.1038/s41418-024-01376-5. Online ahead of print.

Authors

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 Yang⁹, Chunfeng Wang^{10

11

12

13}, Yan Zeng^{14

15

16

17}

Affiliations

¹ College of Veterinary Medicine, Jilin Agricultural University, Changchun, China.
² Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China.
³ Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China.
⁴ Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China.
⁵ College of Veterinary Medicine, Jilin Agricultural University, Changchun, China. xinc@jlau.edu.cn.
⁶ Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China. xinc@jlau.edu.cn.
⁷ Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China. xinc@jlau.edu.cn.
⁸ Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China. xinc@jlau.edu.cn.
⁹ Department of Laboratory Medicine of Huashan Hospital, Fudan University, Shanghai, China. kobesakura@fudan.edu.cn.
¹⁰ College of Veterinary Medicine, Jilin Agricultural University, Changchun, China. wangchunfeng@jlau.edu.cn.
¹¹ Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China. wangchunfeng@jlau.edu.cn.
¹² Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China. wangchunfeng@jlau.edu.cn.
¹³ Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China. wangchunfeng@jlau.edu.cn.
¹⁴ College of Veterinary Medicine, Jilin Agricultural University, Changchun, China. zengyan@jlau.edu.cn.
¹⁵ Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China. zengyan@jlau.edu.cn.
¹⁶ Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China. zengyan@jlau.edu.cn.
¹⁷ Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China. zengyan@jlau.edu.cn.

^# Contributed equally.

PMID: 39266719
DOI: 10.1038/s41418-024-01376-5

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.

Abstract

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