N4BP3 facilitates NOD2-MAPK/NF-κB pathway in inflammatory bowel disease through mediating K63-linked RIPK2 ubiquitination

The NOD2 signaling pathway, which plays an important role in the mechanisms of inflammatory bowel disease (IBD) development, has been closely associated with ubiquitination. It was revealed in this study that NOD2 receptor activation could obviously affect the expression of 19 ubiquitination-related...

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Bibliographic Details
Published in:Cell death discovery 2024-10, Vol.10 (1), p.440-13, Article 440
Main Authors: Jiang, Wang, Zhao, Yan, Han, Min, Xu, Jiafan, Chen, Kun, Liang, Yi, Yin, Jie, Hu, Jinyue, Shen, Yueming
Format: Article
Language:English
Subjects:
631/250/262/2106/2517
692/420/2780/262/2106/2517
692/699/1503/257
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Crohn's disease
Dextran
Dextran sulfate
Extracellular signal-regulated kinase
Immunoprecipitation
Inflammatory bowel disease
Inflammatory bowel diseases
Intestine
Life Sciences
MAP kinase
mRNA
NF-κB protein
NOD2 protein
Receptor mechanisms
Signal transduction
Stem Cells
Transcription activation
Ubiquitination
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Summary:The NOD2 signaling pathway, which plays an important role in the mechanisms of inflammatory bowel disease (IBD) development, has been closely associated with ubiquitination. It was revealed in this study that NOD2 receptor activation could obviously affect the expression of 19 ubiquitination-related genes, with N4BP3 being the most prominently expressed and upregulated. In addition, N4BP3 knockdown was found to reduce the mRNA levels of MDP-induced inflammatory factors, while N4BP3 overexpression elevated their mRNA levels as well as the levels of phospho-ERK1/2, phospho-JNK, phospho-P38 and phospho-NF-κB P65 proteins. Immunoprecipitation tests showed that N4BP3 could pull down RIPK2 and promote its K63-linked ubiquitination. In human tissue specimen assays and mouse experiments, we found that the expression of N4BP3 was significantly elevated in Crohn’s disease (CD) patients and IBD mice, and N4BP3 knockdown reduced the dextran sulfate sodium-induced pathological score and the expression of inflammatory factors in the mouse colon tissue. In conclusion, N4BP3 is able to interact with RIPK2 and promote its K63-linked ubiquitination, to further promote the NOD2-MAPK/NF-κB pathway, thereby increasing promoting the release of inflammation factors and the degree of IBD inflammation.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-024-02213-x