2. Academic Validation
  3. E3 ubiquitin ligase RNF128 negatively regulates the IL-3/STAT5 signaling pathway by facilitating K27-linked polyubiquitination of IL-3Rα

E3 ubiquitin ligase RNF128 negatively regulates the IL-3/STAT5 signaling pathway by facilitating K27-linked polyubiquitination of IL-3Rα

  • Cell Commun Signal. 2024 May 3;22(1):254. doi: 10.1186/s12964-024-01636-4.
Jingge Yu 1 2 3 4,  Jianguo Li 1 2 3,  Ao Shen 1 2 3,  Zhiping Liu 5 6,  Tian-Sheng He 7 8
Affiliations

Affiliations

  • 1 School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China.
  • 2 Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China.
  • 3 School of Graduate, Gannan Medical University, Ganzhou, Jiangxi, China.
  • 4 Department of Blood Transfusion, Jingmen Central Hospital, Jingmen, China.
  • 5 School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China. Zhiping.Liu@gmu.edu.cn.
  • 6 Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China. Zhiping.Liu@gmu.edu.cn.
  • 7 School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China. hetiansheng361@163.com.
  • 8 Center for Immunology, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China. hetiansheng361@163.com.
PMID: 38702781 DOI: 10.1186/s12964-024-01636-4
Abstract

IL-3/STAT5 signaling pathway is crucial for the development and activation of immune cells, contributing to the cellular response to infections and inflammatory stimuli. Dysregulation of the IL-3/STAT5 signaling have been associated with inflammatory and autoimmune diseases characterized by inflammatory cell infiltration and organ damage. IL-3 receptor α (IL-3Rα) specifically binds to IL-3 and initiates intracellular signaling, resulting in the phosphorylation of STAT5. However, the regulatory mechanisms of IL-3Rα remain unclear. Here, we identified the E3 ubiquitin Ligase RNF128 as a negative regulator of IL-3/STAT5 signaling by targeting IL-3Rα for lysosomal degradation. RNF128 was shown to selectively bind to IL-3Rα, without interacting with the common beta chain IL-3Rβ, which shares the subunit with GM-CSF. The deficiency of Rnf128 had no effect on GM-CSF-induced phosphorylation of STAT5, but it resulted in heightened Il-3-triggered activation of STAT5 and increased transcription of the Id1, PIM1, and CD69 genes. Furthermore, we found that RNF128 promoted the K27-linked polyubiquitination of IL-3Rα in a Ligase activity-dependent manner, ultimately facilitating its degradation through the lysosomal pathway. RNF128 inhibited the activation and chemotaxis of macrophages in response to LPS stimulation, thereby attenuating excessive inflammatory responses. Collectively, these results reveal that RNF128 negatively regulates the IL-3/STAT5 signaling pathway by facilitating K27-linked polyubiquitination of IL-3Rα. This study uncovers E3 ubiquitin Ligase RNF128 as a novel regulator of the IL-3/STAT5 signaling pathway, providing potential molecular targets for the treatment of inflammatory diseases.

Keywords

IL-3; Inflammation; Lysosomal degradation; RNF128; Ubiquitination.

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