PDCoV nsp14通过自噬和蛋白酶体途径降解MAVS、MyD88和TRAF3蛋白抑制干扰素通路

doi:10.1016/j.jia.2025.04.015

Journal of Integrative Agriculture ›› 2026, Vol. 25 ›› Issue (9): 3829-3841.DOI: 10.1016/j.jia.2025.04.015

PDCoV nsp14通过自噬和蛋白酶体途径降解MAVS、MyD88和TRAF3蛋白抑制干扰素通路

收稿日期:2024-09-09 修回日期:2025-04-18 接受日期:2025-03-13 出版日期:2026-09-20 发布日期:2026-08-10

PDCoV nsp14 interferes with the interferon pathway by degradin MAVS, MyD88, and TRAF3 proteins via the autophagy and proteasome pathways

Yiyi Song^{1, 2*}, Ning Kong^{1, 2*}, Lanlan Zheng^3*, Yu Zhang^4*, Xueying Zhai¹, Wenzhen Qin¹, Xinyu Yang¹, Xiaoquan Wang¹, Ao Gao³, Wu Tong¹, Changlong Liu¹, Hao Zheng¹, Hai Yu¹, Wen Zhang⁵, Guangzhi Tong^{1, 2}, Tongling Shan^{1, 2#}

¹ Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 201100, China
² Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225000, China
³ College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450000, China
⁴Department of Preventive Dentistry, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 201100, China
⁵ School of Medicine, Jiangsu University, Zhenjiang 212000, China

Received:2024-09-09 Revised:2025-04-18 Accepted:2025-03-13 Online:2026-09-20 Published:2026-08-10
About author:Yiyi Song, E-mail: 1814105954@qq.com; Ning Kong, E-mail: kongning@shvri.ac.cn; Lanlan Zheng, E-mail: lanlan@henau.edu.cn; Yu Zhang, E-mail: zy24ymjulia@163.com; #Correspondence Tongling Shan, E-mail: shantongling@shvri.ac.cn * These authors contributed equally to this study.
Supported by:
This work was supported by grants from the National Key Research and Development Programs of China (2021YFD1801102), the National Natural Science Foundation of China (32272999 and 32102665), the Natural Science Foundation of Shanghai, China (23ZR1476900), and the Youth Innovation Program of Chinese Academy of Agricultural Sciences (Y2022QC28).

摘要/Abstract

摘要：

猪δ冠状病毒（PDCoV）是一种新发的猪肠道冠状病毒，可引起哺乳仔猪急性腹泻、呕吐、脱水和死亡。该病毒不仅严重危害养猪业的健康发展，其潜在的跨物种传播风险更值得关注。PDCoV的非结构蛋白14（nsp14）抑制β干扰素（IFN-β）的机制不清。在本研究中，我们发现PDCoV的nsp14蛋白能够通过泛素-蛋白酶体和自噬-溶酶体途径，特异性靶向降解干扰素信号通路中的关键接头蛋白MAVS、MyD88和TRAF3。PDCoV nsp14通过招募E3泛素连接酶MARCH8介导MAVS、MyD88和TRAF3蛋白的泛素化修饰。泛素化后的蛋白被货物受体NDP52识别，并转运至溶酶体降解，有效抑制IFN-β的表达。这一过程揭示了PDCoV nsp14在抑制天然免疫和促进病毒复制中的重要作用。我们还发现：宿主细胞中的MAVS、MyD88和TRAF3蛋白也能够通过激活NDP52介导的选择性自噬途径降解PDCoV的nsp14蛋白，抑制nsp14拮抗天然免疫。本研究揭示了PDCoV nsp14与宿主蛋白之间的相互博弈机制。一方面，PDCoV nsp14通过选择性自噬途径降解宿主蛋白，抑制宿主的天然免疫，为病毒的复制和增殖创造有利条件；另一方面，宿主细胞通过选择性自噬途径降解PDCoV nsp14蛋白，试图清除病毒并维持自身的免疫防御功能。这种双向蛋白降解机制的发现，不仅阐明了PDCoV免疫逃逸的核心策略，更为理解冠状病毒与宿主的协同进化提供了新视角。本研究为开发靶向病毒免疫逃逸机制的广谱抗冠状病毒药物奠定了理论基础。

Abstract:

Porcine deltacoronavirus (PDCoV) is a newly identified pathogen that can potentially undergo cross-species transmission to threaten the safety of swine and humans. The mechanism by which PDCoV nonstructural protein 14 (nsp14) inhibits the expression of IFN-β is unknown. In this study, we showed that PDCoV nsp14 degrades the MAVS, MyD88 and TRAF3 proteins in host cells by proteasomal and autophagy pathways. PDCoV nsp14 recruits the E3 ubiquitin ligase MARCH8 for catalyzing MAVS, MyD88 and TRAF3 protein ubiquitination. These proteins were recognized and transported to lysosomes by the cargo receptor NDP52 for degradation to inhibit the expression of IFN-β. Furthermore, MAVS, MyD88 and TRAF3 were also found to degrade PDCoV nsp14 by selective autophagy. These results reveal the dual function of selective autophagy in the PDCoV nsp14 and host proteins, which can promote the ubiquitination of viral particles and host antiviral proteins to degrade them both for regulating the relationship between virus infection and host innate immunity.

Key words: PDCoV , nsp14 , interferon , autophagosome , proteasome

. PDCoV nsp14通过自噬和蛋白酶体途径降解MAVS、MyD88和TRAF3蛋白抑制干扰素通路[J]. Journal of Integrative Agriculture, 2026, 25(9): 3829-3841.

Yiyi Song, Ning Kong, Lanlan Zheng, Yu Zhang, Xueying Zhai, Wenzhen Qin, Xinyu Yang, Xiaoquan Wang, Ao Gao, Wu Tong, Changlong Liu, Hao Zheng, Hai Yu, Wen Zhang, Guangzhi Tong, Tongling Shan. PDCoV nsp14 interferes with the interferon pathway by degradin MAVS, MyD88, and TRAF3 proteins via the autophagy and proteasome pathways[J]. Journal of Integrative Agriculture, 2026, 25(9): 3829-3841.

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PDCoV nsp14通过自噬和蛋白酶体途径降解MAVS、MyD88和TRAF3蛋白抑制干扰素通路

PDCoV nsp14 interferes with the interferon pathway by degradin MAVS, MyD88, and TRAF3 proteins via the autophagy and proteasome pathways

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