PIM1 Attenuates Innate Immunity to Foster Coronavirus Replication through Ubiquitin Ligase β-TrCP-Mediated IFNAR1 Degradation.

IF 14.3 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Advanced Science Pub Date : 2025-07-06 DOI:10.1002/advs.202503487

Qianya Wan, Lin Zhu, Cien Chen, Li Zhong, Houying Leung, Wei Li, Chang Xu, Xi Yao, Huan Hu, Mandi Wu, Yuxin Hou, Hin Chu, Yiran Wang, Sheng Chen, Mingyu Pan, Zongwei Cai, Ming-Liang He

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Abstract

Virus infection stimulates proto-oncoprotein PIM1 kinase expression, but its importance and the biological functions of this process are poorly understood. Herein, PIM1 promotes IFNAR1 degradation to attenuate cellular innate immunity during human coronavirus HCoV-OC43 infection. During virus replication, the double-stranded viral RNA and some viral proteins upregulate PIM1 expression, which phosphorylates E3 ubiquitin ligase β-TrCP1 at Serine 82. The pS82-β-TrCP1 then forms a complex with S535/S539-phosphorylated interferon receptor IFNAR1 (pS535/539-IFNAR1), leading to IFNAR1 ubiquitination and degradation. Both pan-inhibitors (CX-6528, SGI-1776, AZD-1208) and a specific inhibitor of PIM1 kinase (PIM1 inhibitor 2) effectively block this process and potently inhibit viral replication. This studies demonstrate a novel strategy that viruses use to disrupt cellular innate immunity, suggesting a potential therapeutic target for further anti-virus drug development.

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通过泛素连接酶β- trcp介导的IFNAR1降解，PIM1减弱先天免疫促进冠状病毒复制

病毒感染刺激原癌蛋白PIM1激酶表达，但其重要性和这一过程的生物学功能尚不清楚。在本研究中，PIM1促进IFNAR1降解以减弱人冠状病毒HCoV-OC43感染期间的细胞先天免疫。在病毒复制过程中，双链病毒RNA和一些病毒蛋白上调PIM1表达，使E3泛素连接酶β-TrCP1丝氨酸82位点磷酸化。然后pS82-β-TrCP1与S535/ s539磷酸化的干扰素受体IFNAR1 （pS535/539-IFNAR1）形成复合物，导致IFNAR1泛素化和降解。两种泛抑制剂（CX-6528、SGI-1776、AZD-1208）和PIM1激酶特异性抑制剂（PIM1 inhibitor 2）都能有效阻断这一过程，并有效抑制病毒复制。这项研究证明了病毒用来破坏细胞先天免疫的一种新策略，为进一步开发抗病毒药物提供了潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY

CiteScore

18.90

自引率

2.60%

发文量

1602

审稿时长

1.9 months

期刊介绍： Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.