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| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Wang, Zengbin Sun, Pei Pan, Banglun Qiu, Jiacheng Zhang, Xiaoxia Shen, Shuling Ke, Xiaoling Tang, Nanhong |
| Abstract | Background Interleukin-33 (IL-33), defined as \"alarming\", exert diverse functions through signaling via the suppression of tumorigenicity 2 (ST2). However, the physiological roles of IL-33/ST2 signaling during acetaminophen (APAP)-induced liver injury are still poorly understood by modern medicine (AILI). This research aims to explore the relationship between IL-33/ST2 and stimulator of interferon (IFN) response cGAMP interactor 1 (STING)-mediated signal transduction. Methods C57BL/6N mice (WT) and IL-33-deficient mice (KO) were intraperitoneally injected with APAP (250 mg/kg). Recombinant IL-33 (500 ng/mouse) and the cGAS/STING inhibitor RU.521 (200 g/kg) were combined to treat AILI. For mechanistic research in vitro, CRISPR-mediated KD technology, immunoprecipitation, mass spectrometry, and immunofluorescence were utilized. Results We discovered that IL-33 deficient mice had increased APAP-induced hepatotoxicity, DNA accumulation, and type 1 IFN production. Mechanistic analysis revealed that IL-33/ST2 enhanced the interaction between Beclin-1 and STING, disrupting STING dimerization, IRF3 phosphorylation, nuclear transport, and IFN-1 gene transcription in HepaRG and Huh7 cells. Beclin-1 interacted with the C-terminus of STING, causing Lys338 acetylation and autophagy degradation of STING. ST2 depletion increased STING signal transduction and IFN-1 promoter activity. Surprisingly, the cGAS/STING inhibitor RU.521 and recombinant IL-33 together improved AILI in vivo. Conclusions These results shed insight on the potential of inhibiting cGAS/STING as a therapy for AILI and emphasize the crucial role of IL-33/ST2 signaling in the regulation of APAP-induced STING signaling. Video Abstract Graphical Abstract |
| Related Links | https://biosignaling.biomedcentral.com/counter/pdf/10.1186/s12964-023-01114-3.pdf |
| Ending Page | 15 |
| Page Count | 15 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| DOI | 10.1186/s12964-023-01114-3 |
| Journal | Cell Communication and Signaling |
| Issue Number | 1 |
| Volume Number | 21 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2023-04-20 |
| Access Restriction | Open |
| Subject Keyword | Cell Biology Protein-Ligand Interactions Receptors Cytokines and Growth Factors IL-33/ST2 Acetaminophen-induced liver injury STING Autophagy Acetylation |
| Content Type | Text |
| Resource Type | Article |
| Subject | Biochemistry Cell Biology Molecular Biology |
| Journal Impact Factor | 8.2/2023 |
| 5-Year Journal Impact Factor | 8/2023 |
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