A collaborative study led by Professor He Mingliang’s team at City University of Hong Kong (CityU) and Professor Cai Zongwei’s team at Hong Kong Baptist University (HKBU), published in Advanced Science (“PIM1 Attenuates Innate Immunity to Foster Coronavirus Replication through Ubiquitin Ligase β-TrCP-Mediated IFNAR1 Degradation”), reveals a groundbreaking immune evasion strategy employed by β-coronaviruses (including SARS-CoV-2 and HCoV-OC43):
- PIM1 Stimulation: Infection by β-coronaviruses triggers a >10-fold increase in host PIM1 kinase expression.
- Innate Immunity Attenuation: PIM1 phosphorylates ubiquitin ligase β-TrCP1 (at Ser82), inducing K63-linked ubiquitination and lysosomal degradation of the IFNAR1 receptor. This disrupts type I interferon signaling and cripples antiviral immunity.
- Therapeutic Efficacy: Pharmacological inhibition of PIM1 reduces viral replication by 90%.
Scientific Significance:
This work, for the first time, provides evidence of viral immune escape via a “host kinase hijacking → E3 ligase modification → immune receptor degradation” cascade. It solves the mystery of impaired interferon signaling in severe COVID-19 patients, identifies PIM1 as a promising antiviral target: PIM1 inhibitors effectively restore innate immunity. This paves the way for developing broad-spectrum anti-coronavirus therapeutics resistant to viral mutations.
Key Contributors:
Dr Qianya Wan (CityU)
Mr Chen Cien (PhD candidate, CityU)
Dr Lin Zhu (HKBU)
Ms Liang Qiaoying (TPg student, CityU)
Funding:
Supported by internal grants from City University of Hong Kong and the Science and Technology Innovation Committee of Shenzhen Municipality.
香港城市大學（城大）何明亮教授團隊與香港浸會大學（浸大）蔡宗葦教授團隊合作，近日在《Advanced Science》刊發一項重要研究 「PIM1 Attenuates Innate Immunity to Foster Coronavirus Replication through Ubiquitin Ligase β-TrCP-Mediated IFNAR1 Degradation」，揭示冠狀病毒免疫逃逸新機制：
- PIM1 激酶上調：β冠狀病毒（含SARS-CoV-2、HCoV-OC43）感染宿主後，PIM1激酶表達激增10倍以上。
- 抑制先天免疫：PIM1 通過磷酸化泛素連接酶 β-TrCP1（S82位點），觸發 IFNAR1 受體 K63 泛素化降解。該過程阻斷 I 型干擾素訊號傳導，導致抗病毒免疫反應失效。
- 治療潛力：抑制 PIM1 可使病毒複製率下降90%。
本研究具有重大了科學意義：首次證實病毒可通過「劫持宿主激酶 → 修飾 E3 連接酶 → 降解免疫受體」的級聯機制實現免疫逃逸；進一步揭示了重症 COVID-19 患者干擾素訊號受損之謎；並確立了 PIM1 為一個具潛力的抗病毒靶點。PIM1 抑製劑可有效恢復先天免疫功能，為研發能抵禦變異株的廣譜抗冠狀病毒藥物提供新方向。
本項研究由城大內部研究基金及深圳市科技創新委員會資助。主要參與人包括城大萬乾婭博士、博士研究生陳賜恩以及浸大朱林博士。 此外，城大授課制碩士研究生梁巧盈同學也深度參與了該專案。