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

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

  • Adv Sci (Weinh). 2025 Jul 6:e03487. doi: 10.1002/advs.202503487.
Qianya Wan 1,  Lin Zhu 2,  Cien Chen 1,  Li Zhong 2,  Houying Leung 1,  Wei Li 3,  Chang Xu 3 4,  Xi Yao 1,  Huan Hu 1,  Mandi Wu 1,  Yuxin Hou 5,  Hin Chu 5,  Yiran Wang 1,  Sheng Chen 1,  Mingyu Pan 1 6,  Zongwei Cai 2,  Ming-Liang He 1 7
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences and Tung Biomedical Sciences Center, City University of Hong Kong, Hong Kong, 999077, China.
  • 2 State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, 999077, China.
  • 3 Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Shandong, 264200, China.
  • 4 College of Medical Laboratory, Dalian Medical University, Dalian, Liaoning, 116044, China.
  • 5 State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 999077, China.
  • 6 School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
  • 7 CityU Shenzhen Research Institute, Nanshan, Shenzhen, 518057, China.
PMID: 40619619 DOI: 10.1002/advs.202503487
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

IFNAR1; PIM1; ubiquitination; β‐TrCP1; β‐coronavirus.

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