JOURNAL OF IMMUNOLOGY
·
2025
·
IF 3.4
Huang Wenji,Wang Yafang,Ji Ning,Xiao Hehe,Chen Kangyong,Guo Jiahong,Feng Jianhua,Mustafa Nageen,Wang Junya,Feng Hao,Zou Jun
A balanced IFN response, tightly regulated at multiple levels, is essential for host defense against viral infection. Tripartite motif-containing (TRIM) proteins are a large group of E3 ubiquitin ligases, and have been shown to be involved in the regulation of IFN response. However, the regulatory functions of individual TRIM proteins remain controversial. Here, we show that a virus-inducible TRIM2 homolog acts as a negative regulator for IFN production in zebrafish. Zebrafish Trim2a was upregulated in response to spring viremia of carp virus (SVCV) infection, and knockout of Trim2a significantly increased the expression of antiviral genes, leading to enhanced resistance to SVCV. Overexpression of Trim2a resulted in pronounced ubiquitination of IFN regulatory factor 3 (IRF3) via K11, K27, K29, and K48, promoting IRF3 degradation and stability of SVCV phosphoprotein to favor viral replication. Moreover, TRIM2a induced ubiquitination of autophagic cargo receptor p62, which then interacted with IRF3, instigating IRF3 degradation. Further, the inhibitory effects of TRIM2a on IFN production were also observed in human HEK293 cells, suggesting that the regulatory functions of TRIM2 are likely to be conserved during evolution. Collectively, our findings demonstrate that TRIM2a is a negative regulator of IFN production, and could serve as a potential target to dampen exacerbated IFN response triggered by aberrant activation of retinoic acid-inducible gene 1 (RIG-I)-like receptors. Our study provides insights into a previously uncharacterized role of TRIM2 in the regulation of IFN signaling.
研究领域:
免疫学
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病毒学
·
分子生物学
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DOI
PubMed
高影响因子
Frontiers in Immunology
·
2022
·
IF 8.786
Xin Zhao,Wenji Huang,Yanjie Shi,Jiahong Guo,Hehe Xiao,Ning Ji,Jianhua Feng,Huifeng Dang,Jun Zou
PLAAT1 is a member of the PLAAT protein family and plays important roles in tumor suppression, transglutaminase activation and peroxisomal biogenesis. Recently, PLAAT1 has been shown to promote degradation of p53 protein and cellular organelles such as mitochondria, endoplasmic reticulum and lysosome. In this study, we show that PLAAT1 inhibits the production of type I interferon and promotes virus replication in zebrafish. Overexpression of Plaat1 in zebrafish cells suppresses antiviral responses and promotes virus replication. Mechanistically, PLAAT1 interacts with IRF3 and IRF7 to initiate degradation of IRF3 and IRF7, which can be attenuated by 3-methyladenine, an inhibitor of autophagosome. Our study provides novel insights into the functions of PLAAT1 in host immune response to viral infection.
研究领域:
免疫学
·
病毒学
·
分子生物学
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DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Zhen Tong,Jia-Peng Zou,Su-Yun Wang,Wei-Wei Luo,Yan-Yi Wang
Interferons (IFNs) activate JAK-STAT pathways to induce downstream effector genes for host defense against invaded pathogens and tumors. Here both type I (β) and II (γ) IFNs are shown that can activate the transcription factor IRF3 in parallel with STAT1. IRF3-deficiency impairs transcription of a subset of downstream effector genes induced by IFN-β and IFN-γ. Mechanistically, IFN-induced activation of IRF3 is dependent on the cGAS-STING-TBK1 axis. Both IFN-β and IFN-γ cause mitochondrial DNA release into the cytosol. In addition, IFNs induce JAK1-mediated tyrosine phosphorylation of cGAS at Y214/Y215, which is essential for its DNA binding activity and signaling. Furthermore, deficiency of cGAS, STING, or IRF3 impairs IFN-β- or IFN-γ-mediated antiviral and antitumor activities. The findings reveal a novel IRF3 activation pathway parallel with the canonical STAT1/2 activation pathways triggered by IFNs and provide an explanation for the pleiotropic roles of the cGAS-STING-IRF3 axis in host defense.
研究领域:
免疫学
·
分子生物学
·
微生物学
·
癌症研究
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DOI
PubMed
高影响因子
EMBO REPORTS
·
2024
·
IF 6.5
ZengXianhuang,XuJiaqi,LiuJiaqi,LiuYang,YangSiqi,HuangJunsong,FanChengpeng,GuoMingxiong,SunGuihong
Viral infection activates the transcription factors IRF3 and NF-κB, which induce type I interferon (IFN) and antiviral innate immune responses. Here, we identify dual-specific tyrosine phosphorylation-regulated kinase 4 (DYRK4) as an important regulator of virus-triggered IFN-β induction and antiviral innate immunity. Overexpression of DYRK4 enhances virus-triggered activation of IRF3 and type I IFN induction, whereas knockdown or knockout of DYRK4 impairs virus-induced activation of IRF3 and NF-κB. Moreover, Dyrk4-knockout mice are more susceptible to viral infection. The underlying mechanism involves DYRK4 acting as a scaffold protein to recruit TRIM71 and LUBAC to IRF3, increasing IRF3 linear ubiquitination, maintaining IRF3 stability and activation during viral infection, and promoting the IRF3-mediated antiviral response. Our findings provide new insights into the molecular mechanisms underlying viral infection-triggered IRF3 stabilization and activation.
研究领域:
免疫学
·
病毒学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2024
·
IF 4.1
Yanwei Zhang,Jing Cen,Haixia Wu,Wa Gao,Zhiying Jia,Mikolaj Adamek,Jun Zou
HnRNP A/B belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family and plays an important role in regulating viral protein translation and genome replication. Here, we found that overexpression of hnRNP A/B promoted Spring viremia of carp virus (SVCV) and Cyprinid herpesvirus 3 (CyHV3) replication. Further, hnRNP A/B was shown to act as a negative regulator of type I interferon (IFN) response. Mechanistically, hnRNP A/B interacted with MITA, TBK1 and IRF3 to initiate their degradation. In addition, hnRNP A/B bound to the kinase domain of TBK1, the C terminal domain of MITA and IAD domain of IRF3, and the RRM1 domain of hnRNP A/B bound to TBK1, RRM2 domain bound to IRF3 and MITA. Our study provides novel insights into the functions of hnRNP A/B in regulating host antiviral response.
研究领域:
分子生物学
·
病毒学
·
免疫学
·
鱼类病理学
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DOI
PubMed
高影响因子
INFLAMMATION
·
2023
·
IF 5.1
Xing Zeyu,Zhen Yanhua,Chen Jie,Du Mingyang,Li Dongdong,Liu Ruyin,Zheng Jiahe
Atherosclerosis (AS), characterized by a maladaptive inflammatory response, is one of the most common causes of death among the elderly. Karyopherin subunit alpha 2 (KPNA2), a member of the nuclear transport protein family, has been reported to play a pro-inflammatory role in various pathological processes by regulating the nuclear translocation of pro-inflammatory transcription factors. However, the function of KPNA2 in AS remains unknown. ApoE −/− mice were fed high-fat diets for 12 weeks to establish an AS mice model. Human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) to establish an AS cell model. We found that KPNA2 was upregulated in the aortic roots of atherosclerotic mice and LPS-stimulated cells. KPNA2 knockdown inhibited LPS-induced secretion of pro-inflammatory factors and monocyte-endothelial adhesion in HUVECs, whereas KPNA2 overexpression exerted the opposite effects. p65 and interferon regulatory factor 3 (IRF3), the transcription factors known to regulate the transcription of pro-inflammatory genes, interacted with KPNA2, and their nuclear translocations were blocked following KPNA2 silencing. Furthermore, we found that KPNA2 protein level was decreased by E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBXW7), which was downregulated in the atherosclerotic mice. FBXW7 overexpression induced ubiquitination with subsequent proteasomal degradation of KPNA2. Meanwhile, the effects of KPNA2 deficiency on atherosclerotic lesions were further confirmed by in vivo experiments. Taken together, our study indicates that KPNA2 downregulation, regulated by FBXW7, may alleviate endothelial dysfunction and related inflammation in the progression of AS by suppressing the nuclear translocation of p65 and IRF3.
研究领域:
心血管疾病
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分子生物学
·
细胞生物学
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病理学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 13
·e70688
·
IF 4.2
Li‐Ping Kang,Cong Xu,Pan Xu,Dong‐Hui Huang,Ze‐Bo Jiang
Non‐small cell lung cancer (NSCLC) stands as a predominant cause of cancer‐related mortality worldwide. Brazilin, an active isoflavonoid compound derived from Chinese herbs, has displayed anti‐cancer properties across various cancer cell lines. However, the precise anti‐tumour mechanism of Brazilin in NSCLC remains incompletely understood. In this paper, we demonstrated that Brazilin treatment significantly reduced the proliferation of NSCLC cells and induced apoptosis. Additionally, Brazilin caused G2 cell cycle arrest in NSCLC cells, characterised by decreased expression of Cyclin B1 and increased expression of P21. Brazilin also induced mitochondrial dysfunction and ROS production in NSCLC cells. Mechanistically, Brazilin treatment significantly activated the STING pathway and upregulated the expression of CXCL10, CXCL9, and CCL5 in NSCLC cell lines. Notably, the inhibition of the STING pathway with H‐151 enhances cell viability, suggesting STING is involved in Brazilin‐induced apoptosis. These findings underscore Brazilin as a promising anti‐cancer agent for NSCLC.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
ARCHIVES OF VIROLOGY
·
2024
·Vol. 169
·期 4
·1-10
·
IF 2.5
Yuan Juan,Pan Jianli,Zhang Xiaofang,Gao Rui
Triple motif protein 21 (TRIM21) has an antiviral function that inhibits various viral infections. However, its role in the progress of influenza A virus (IAV) infection is unclear. In this study, we investigated the role and molecular mechanism of TRIM21 in IAV infection. RT-qPCR was used to determine the level of TRIM21 mRNA, and ELISA was used to measure the levels of IFN-α, IFN-β, IL-6, and TNF-α. The levels of the TRIM21, NP, TBK1, IRF3, p-TBK1, and p-IRF3 proteins were estimated by Western blot. The results showed that, after IAV infection, TRIM21 was upregulated in clinical patient serum and A549 cells, and this was correlated with the IFN response. Overexpression of TRIM21 reduced IAV replication and transcription in in vitro cell experiments. TRIM21 also increased IFN-α and IFN-β levels and decreased IL-6 and TNF-α levels in A549 cells. In addition, overexpression of TRIM21 inhibited IAV-induced apoptosis. Further experiments demonstrated that TBK1-IRF3 signaling was activated by TRIM21 and was involved in the inhibitory effect of TRIM21 on virus replication. In summary, our study suggests that TRIM21 inhibits viral replication by activating the TBK1-IRF3 signaling pathway, further inhibiting the infection process of IAV.
CAS / MDL:
研究领域:
病毒学
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免疫学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2026
·
IF 8.4
Li Shuo,Xu Bing,Lu Ming-jun,Wu Qian-wen,Qin Wen-qing,Dai Zi-qi,Li Xiao-jiao-yang,Bai Jin-zhao,Lei Hai-min,Liu Run-ping
The severe inflammation associated with infectious or inflammatory diseases significantly contributes to mortality. Interferon regulatory factor 3 (IRF3) represents a potential anti-inflammatory target, but the development of IRF3 inhibitors has not yielded satisfactory results to date. In this study, we established a phenotype-based high-throughput screening system to conduct activity-guided hierarchical screening of clinical frequently used anti-inflammatory and anti-rheumatic herbal extracts and compounds. Employing a Gaussia-luciferase reporter system driven by the IFNB1 promoter, we identified sinomenine as a potent type I interferon (IFN) inhibitor from a set of 28 anti-inflammatory herbal products. Furthermore, among 24 synthesized sinomenine derivatives modified by various electrophilic groups, Sim-9 (2.5–10 μM) dose-dependently inhibited IFN responses triggered by TLRs, RLRs, and STING activation in mouse RAW264.7 cells and in human THP-1 cells, HT-29 cells and A549 cells. We demonstrated that Sim-9, by covalently binding to Cys222, induced a conformational change in the p LxIS motif-binding surface of IRF3, thus blocking its interaction with upstream adapters, including TRIF, MAVS and STING, and subsequent homodimerization of IRF3 itself, which were all essential for activation of type I IFN responses. In in vivo experiments, we showed that injection of Sim-9 (30, 60 mg/kg, i.p.) effectively protected against devastating inflammation in cecal ligation and puncture (CLP)-induced sepsis in mice, and improved cerulein-induced pancreatitis by inhibiting IRF3. Our study discovers Sim-9 as a novel covalent allosteric inhibitor of IRF3 and reveals that the p LxIS motif binding surface represents a previously uncharacterized druggable target for IRF3 activation, providing a promising therapeutic strategy for the treatment of severe inflammatory injuries.
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DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Ke Yang,Shuaining Chai,Helong Song,Sinan Cao,Fangmiao Gao,Chenxuan Zhou,Linwei Li
Esophageal carcinoma (EC) is one of the most common malignant tumors in the world. ECRG4 has been recently discovered to be downregulated in EC. However, the mechanism leading to reduced expression of ECRG4 in esophageal cancer remains obscure. Here, we found that ECRG4 expression was significantly downregulated in EC tissues and cell lines. ECRG4 overexpression led to a significant decrease in proliferation in vitro and in vivo . Mechanistically, ECRG4 can activate IRF3/IFN-γ pathway. IFN-γ can promote the expression of miR-29b. MiR-29b reduces the expression of DNMT1. DNMT1 may affect the expression of ECRG4 by affecting the methylation of ECRG4 promoter. These results reveal ECRG4/IRF3/IFN-γ/miR-29b/DNMT1 positive feedback loop in esophageal carcinoma cells, which may become a potential therapeutic target for esophageal carcinoma.
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DOI
PubMed
高影响因子
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
·
2025
·
IF 1.8
Jiaojiao Ren,Jun Ying,Haijian Liu,Shanshan Hu,Jiangdong Li,Danfei Zhou
Background: This study was designed to explore the action mechanism of stimulator of interferon genes (STING) on the differentiation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment of lung cancer.Methods: Bioinformatics analysis yielded a potential pathway for STING to regulate MDSC differentiation, the interferon regulatory factor 3 (IRF3)/NF-κB axis. The transfection efficiency of STING overexpression plasmid and small interfering RNA against IRF3 (siIRF3) was examined by quantitative real-time polymerase chain reaction (qRT-PCR). After transfection, A9 cells were co-cultured with extracted bone marrow cells (BMCs). MDSC differentiation, protein expression of the IRF3/NF-κB pathway, and changes in nuclear translocation of NF-κB were analyzed by flow cytometry, Western blot, and immunofluorescence staining experiments. A transplanted tumor mouse model was used for in vivo experiments. After cyclic diadenyl monophosphate (CDA; STING agonist) treatment, changes in MDSC differentiation and protein expression of the IRF3/NF-κB axis in transplanted tumors were verified by immunohistochemical staining, qRT-PCR, and Western blot.Results: Coculture of A9 cells and BMCs promoted MDSC differentiation, inhibited activation of IRF3/NF-κB signal in A9 cells, and boosted nuclear translocation of NF-κB. However, after the upregulation of STING, IRF3/NF-κB signal was activated, while MDSC differentiation and nuclear translocation of NF-κB were inhibited. SiIRF3 reversed the effects of STING overexpression. In vivo, CDA dampened MDSC differentiation and promoted protein expression of the IRF3/NF-κB axis.Conclusion: STING signal in lung cancer cells inhibits MDSC differentiation through activation of the IRF3/NF-κB pathway.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Sheng Zhang,Rongrong Huang,Junsong Jing,Xueping Wei,Yu Zhang,Youping Wu,Guoteng Ou,Jingjin Hu,Yueguo Wu,Yuanyuan Li,Shibo Ying,Zhenqiang You
ABSTRACT Background Acute respiratory distress syndrome (ARDS) is an acute respiratory disease characterized by bilateral chest radiolucency and severe hypoxemia. Quzhou Fructus Aurantii ethyl acetate extract (QFAEE), which is prepared from the traditional Chinese respiratory anti-inflammatory natural herb Quzhou Fructus Arantii, has the potential to alleviate ARDS. In this work, we aimed to investigate the potential and mechanism underlying the action of QFAEE on ARDS and how QFAEE modulates the STING pathway to reduce type I interferon release to alleviate the inflammatory response. Methods Lipopolysaccharide (LPS), a potential proinflammatory stimulant capable of causing pulmonary inflammation with edema after nasal drops, was employed to model ARDS in vitro and in vivo . Under QFAEE intervention, the mechanism of action of QFAEE to alleviate ARDS was explored in this study. TREX1 −/− mice were sued as a research model for the activation of the congenital STING signaling pathway. The effect of QFAEE on TREX1 −/− mice could explain the STING-targeted effect of QFAEE on alleviating the inflammatory response. Our explorations covered several techniques, Western blot, histological assays, immunofluorescence staining, transcriptomic assays and qRT-PCR to determine the potential mechanism of action of QFAEE in antagonizing the inflammatory response in the lungs, as well as the mechanism of action of QFAEE in targeting the STING signaling pathway to regulate the release of type I interferon. Results QFAEE effectively alleviates ARDS symptoms in LPS-induced ARDS. We revealed that the mechanism underlying LPS-induced ARDS is the STING-TBK1 signaling pathway and further elucidated the molecular mechanism of QFAEE in the prevention and treatment of ARDS. QFAEE reduced the release of type I interferons by inhibiting the STING-TBK1-IRF3 axis, thus alleviating LPS-induced pneumonia and lung cell death in mice. Another key finding is that activation of the STING pathway by activators or targeted knockdown of the TREX1 gene can also induce ARDS. As expected, QFAEE was found to be an effective protective agent in alleviating ARDS and the antagonistic effect of QFAEE on ARDS was achieved by inhibiting the STING signaling pathway. Conclusions The main anti-inflammatory effect of QFAEE was achieved by inhibiting the STING signaling pathway and reducing the release of type I interferons. According to this mechanism of effect, QFAEE can effectively alleviate ARDS and can be considered a potential therapeutic agent. In addition, the STING pathway plays an essential role in the development and progression of ARDS, and it is a potential target for ARDS therapy.
研究领域:
药理学
·
免疫学
·
呼吸医学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）