STK39 inhibits antiviral immune response by inhibiting DCAF1-mediated PP2A degradation.
10.1016/j.apsb.2024.12.034
- Author:
Chengfei ZHANG
1
;
Ping XU
2
;
Yongsheng WANG
3
;
Xin CHEN
1
;
Yue PAN
1
;
Zhijie MA
4
;
Cheng WANG
3
;
Haojun XU
5
;
Guoren ZHOU
6
;
Feng ZHU
1
;
Hongping XIA
7
Author Information
1. Department of General Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China.
2. The Second Hospital Affiliated Wannan Medical College, Wuhu 241000, China.
3. Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210009, China.
4. Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310020, China.
5. National Health Commission Key Laboratory of Antibody Techniques & Department of Pathology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
6. Jiangsu Cancer Hospital, the Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing 210009, China.
7. Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing 210009, China.
- Publication Type:Journal Article
- Keywords:
DCAF1;
IRF3;
Immune escape;
PP2A;
PPP2R1A;
STK39;
Type I interferon;
Viral infection
- From:
Acta Pharmaceutica Sinica B
2025;15(3):1535-1551
- CountryChina
- Language:English
-
Abstract:
Evading host immunity killing is a critical step for virus survival. Inhibiting viral immune escape is crucial for the treatment of viral diseases. Serine/threonine kinase 39 (STK39) was reported to play an essential role in ion homeostasis. However, its potential role and mechanism in viral infection remain unknown. In this study, we found that viral infection promoted STK39 expression. Consequently, overexpressed STK39 inhibited the phosphorylation of interferon regulatory factor 3 (IRF3) and the production of type I interferon, which led to viral replication and immune escape. Genetic ablation or pharmacological inhibition of STK39 significantly protected mice from viral infection. Mechanistically, mass spectrometry and immunoprecipitation assays identified that STK39 interacted with PPP2R1A (a scaffold subunit of protein phosphatase 2A (PP2A)) in a kinase activity-dependent manner. This interaction inhibited DDB1 and CUL4 associated factor 1 (DCAF1)-mediated PPP2R1A degradation, maintained the stabilization and phosphatase activity of PP2A, which, in turn, suppressed the phosphorylation of IRF3, decreased the production of type I interferon, and then strengthened viral replication. Thus, our study provides a novel theoretical basis for viral immune escape, and STK39 may be a potential therapeutic target for viral infectious diseases.
