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

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

doi:10.1002/advs.202503487

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

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.

Original language	English
Article number	e03487
Number of pages	14
Journal	Advanced Science
Volume	12
Issue number	37
Early online date	6 Jul 2025
DOIs	https://doi.org/10.1002/advs.202503487
Publication status	Published - 6 Oct 2025

User-Defined Keywords

β-TrCP1
β-coronavirus
IFNAR1
PIM1
ubiquitination

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10.1002/advs.202503487

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Wan, Q., Zhu, L., Chen, C., Zhong, L., Leung, H., Li, W., Xu, C., Yao, X., Hu, H., Wu, M., Hou, Y., Chu, H., Wang, Y., Chen, S., Pan, M., Cai, Z., & He, M. L. (2025). PIM1 Attenuates Innate Immunity to Foster Coronavirus Replication through Ubiquitin Ligase β-TrCP-Mediated IFNAR1 Degradation. Advanced Science, 12(37), Article e03487. https://doi.org/10.1002/advs.202503487

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title = "PIM1 Attenuates Innate Immunity to Foster Coronavirus Replication through Ubiquitin Ligase β-TrCP-Mediated IFNAR1 Degradation",

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.",

keywords = "β-TrCP1, β-coronavirus, IFNAR1, PIM1, ubiquitination",

author = "Qianya Wan and Lin Zhu and Cien Chen and Li Zhong and Houying Leung and Wei Li and Chang Xu and Xi Yao and Huan Hu and Mandi Wu and Yuxin Hou and Hin Chu and Yiran Wang and Sheng Chen and Mingyu Pan and Zongwei Cai and He, {Ming liang}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. Funding Information: The work was partially supported by grants from the Science Technology and Innovation Committee of Shenzhen Municipality [JCYJ20180507181627057]; the RGC General Research Fund of Hong Kong Special Administrative Region [11104020] and Strategic funds from the City University of Hong Kong to M. He; Tier 1 startup fund of Hong Kong Baptist University (HKBU) 162874, and donation from the Kwok Chung Bo Fun Charitable Fund for the establishment of the Kwok Yat Wai Endowed Chair of Environmental and Biological Analysis. Hong Kong Scholars Program(XJ2022044).",

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T1 - PIM1 Attenuates Innate Immunity to Foster Coronavirus Replication through Ubiquitin Ligase β-TrCP-Mediated IFNAR1 Degradation

AU - Wan, Qianya

AU - Zhu, Lin

AU - Chen, Cien

AU - Zhong, Li

AU - Leung, Houying

AU - Li, Wei

AU - Xu, Chang

AU - Yao, Xi

AU - Hu, Huan

AU - Wu, Mandi

AU - Hou, Yuxin

AU - Chu, Hin

AU - Wang, Yiran

AU - Chen, Sheng

AU - Pan, Mingyu

AU - Cai, Zongwei

AU - He, Ming liang

N1 - Publisher Copyright: © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. Funding Information: The work was partially supported by grants from the Science Technology and Innovation Committee of Shenzhen Municipality [JCYJ20180507181627057]; the RGC General Research Fund of Hong Kong Special Administrative Region [11104020] and Strategic funds from the City University of Hong Kong to M. He; Tier 1 startup fund of Hong Kong Baptist University (HKBU) 162874, and donation from the Kwok Chung Bo Fun Charitable Fund for the establishment of the Kwok Yat Wai Endowed Chair of Environmental and Biological Analysis. Hong Kong Scholars Program(XJ2022044).

PY - 2025/10/6

Y1 - 2025/10/6

N2 - 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.

AB - 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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DO - 10.1002/advs.202503487

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AN - SCOPUS:105009785973

SN - 2198-3844

VL - 12

JO - Advanced Science

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M1 - e03487

ER -

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

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