Advanced Science
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2024
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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
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分子生物学
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微生物学
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癌症研究
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DOI
PubMed
高影响因子
VETERINARY RESEARCH
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2025
·Vol. 56
·期 1
·1-17
·
IF 3.5
Zhang Yanwei,Jia Zhao,Yuan Gaoliang,Chen Kangyong,Cen Jing,Wang Junya,Feng Hao,Adamek Mikolaj,Zou Jun
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of 34–120 kDa nuclear proteins that have recently been reported to participate in virus replication. The hnRNP family contains approximately 20 members, including hnRNP A1, hnRNP A2, hnRNP A2B1, hnRNPC, hnRNPD and hnRNPK. HnRNPC plays important roles in RNA biology, including expression, stability, mRNA splicing, nonspecific sequence export and 3’-end processing; however, the mechanisms underlying hnRNPC regulatory roles are not fully understood. Here, we found that zebrafish hnRNPC promoted spring viraemia of carp virus (SVCV) replication by increasing the stability of SVCV phosphoprotein while inhibiting the K48-linked ubiquitination of virus phosphoprotein, thereby suppressing the type I interferon (IFN) response. Mechanistically, hnRNPC could interact with the mediator of IFN regulatory factor 3 activation (MITA) to activate K48-linked ubiquitination for MITA degradation through the C-terminal domain of hnRNPC. We also showed that human hnRNPC could interact with MITA and that the overexpression of human hnRNPC decreased MITA protein in HEK293 cells, suggesting that the negative regulatory effects of hnRNPC on the type I IFN response are evolutionarily conserved. Collectively, our data indicate that hnRNPC promotes virus replication by suppressing IFN production activated by MITA and increasing the availability of viral proteins. Our work reveals an evolutionarily conserved mechanism that controls the IFN-mediated antiviral response by a member of the hnRNP family in vertebrates.
研究领域:
病毒学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
·
2025
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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
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分子生物学
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DOI
PubMed
高影响因子
Cell Discovery
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2025
·Vol. 11
·期 1
·1-14
·
IF 12.5
Wang Jinrui,Niu Shenghui,Hu Xiao,Li Tianxing,Liu Shengduo,Tu Yingfeng,Shang Zehua,Zhao Lin,Xu Pinglong,Lin Jingwen,Chen Lu,Billadeau Daniel D.,Jia Da
The cGAS-STING pathway mediates the innate immune response to cytosolic DNA, contributing to surveillance against microbial invasion or cellular damage. Once activated, STING recruits TBK1 at the trans-Golgi network (TGN), which in turn phosphorylates IRF3 to induce type I interferon (IFN-I) expression. In contrast to STING, little is known about how TBK1 is transported to the TGN for activation. Here, we show that multiple TGN tethering factors, a group of proteins involved in vesicle capturing, are indispensable for STING-IFN-I signaling. Deletion of TBC1D23, a recently reported tethering factor, in mice impairs the STING-IFN-I signaling, but with insignificant effect on STING-NF-κB signaling. Mechanistically, TBC1D23 interacts with TBK1 via the WASH complex subunit FAM21 and promotes its endosome-to-TGN translocation. Furthermore, multiple TGN tethering factors were reduced in aged mice and senescent fibroblasts. In summary, our study uncovers that TGN tethering factors are key regulators of the STING-IFN-I signaling and suggests that their reduction in senescence may produce aberrant STING signaling.
研究领域:
免疫学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
BIOCONJUGATE CHEMISTRY
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2018
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IF 4.485
Yali Hu,Yingqin Hou,Hao Wang,Hua Lu
The performance of many therapeutic proteins, including human interferon-α2b (IFN), is often impeded by their intrinsic instability to protease, poor pharmacokinetics, and strong immunity. Although PEGylation has been an effective approach to improve the pharmacokinetics of many proteins, a few noticeable limitations have aroused vast research efforts in seeking alternatives to PEG for bioconjugation. Herein, we report our investigation on the use of polysarcosine (PSar), a nonionic and hydrophilic polypeptoid, for IFN modification. The site-specific conjugate PSar-IFN, generated by native chemical ligation in high yield, is systematically compared with a similarly produced PEG–interferon conjugate (PEG-IFN) to evaluate the in vitro and in vivo behaviors. PSar is found to show comparable ability in stabilizing IFN from protease digestion in vitro and prolonging the circulation half-life in vivo. Interestingly, PSar-IFN retains more activity in vitro and accumulates more in the tumor sites upon systemic administration than PEG-IFN. Most importantly, PSar-IFN is significantly more potent in inhibiting tumor growth and elicits considerably less anti-IFN antibodies in mouse than PEG-IFN. Together, our results demonstrate for the first time that PSar is an outstanding candidate for therapeutic protein conjugation. Considering the low toxicity, biodegradability, and excellent stealth effect of PSar, this study suggests that such polypeptoids hold enormous potential for many biomedical applications including protein delivery, colloidal stabilization, and nanomedicine.
研究领域:
药物化学
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生物医学工程
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分子生物学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
IEEE SENSORS JOURNAL
·
2024
·
IF 4.3
Zhikang Rao,Boyu Guo,Jixiang Zu,Weiqiang Zheng,Ying Xu,Yuting Yang
In clinical diagnosis, the detection of dopamine (DA) is often interfered by epinephrine (EP), a neurotransmitter drug that shares a similar structure with DA, which affects the accurate prediction of DA concentration. In this study, an electrochemiluminescence (ECL) and differential pulse voltammetry (DPV) dual model biosensor combined with machine learning algorithm was proposed for improving the selective detection of DA under EP interference. First, reduced graphene and gold nanoparticles were applied to enhance the sensitivity and stability of the sensor in ECL and DPV measurement. Compared with single model sensing, the dual model sensor could combine the superiority of ECL and DPV while improving the accuracy and reliability of experimental data. Then, nine graphic features related to concentration prediction were extracted from the ECL and DPV response curves, and Pearson’s correlation coefficient (PCC), as well as random forest (RF) algorithm, was adopted for feature importance analysis. To achieve accurate signal decoupling, an intelligent biologically inspired algorithm, particle swarm optimization (PSO) algorithm, was introduced to optimize initial weights and thresholds of the traditional artificial neural network (ANN) for further model training based on multi-feature fusion, which greatly increased the prediction accuracy of DA in the presence of EP. The results demonstrated that DA could be accurately predicted in the concentration range of 9– 200 μM , and the R2 between the true and predicted values of DA concentration reached 0.99. The root-mean-square error (RMSE) and mean absolute error (MAE) of the test dataset were 5.77 and 4.32 μM , respectively. In addition, the PSO-ANN-assisted ECL-DPV dual model detection scheme has been successfully applied for the determination of DA in real samples, such as goat serum and artificial urine.
研究领域:
生物医学工程
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临床诊断
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电化学传感
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产品关联
DOI
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
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病毒学
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分子生物学
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DOI
PubMed
高影响因子
CHEMOSPHERE
·
2021
·
IF 7.086
Lei Liu,Huan Wang,Meng Xu,Tian-Xiu Qiu,Jiong Chen
Azoxystrobin (AZ) has entered aquatic ecosystems and produced serious damages to fish associated with potentially increasing the susceptibility to pathogens . This study characterized the defense abilities of fish by exposed to AZ on challenging with the infection of spring viraemia of carp virus (SVCV). The results showed that SVCV replication increased significantly in EPC cells and zebrafish that were exposed to up to 50 μg/L of AZ at 3, 5, 7, and 14 d. Intracellular biochemical assays indicated that AZ at 5 and 50 μg/L inhibited the activation of Nrf2-ARE pathway including a decrease in Nrf2 expression, Nrf2 phosphorylation, HO-1 content, and three antioxidant activities. While no significant difference in ERK1/2 and JNK MAPKs in zebrafish was observed, P38 phosphorylation was significantly decreased at 7 and 14 d, and the changes in MAPKs were more evident in EPC cells previously exposed to AZ at 7 d. These results revealed that AZ initially induced low phosphorylation of MAPKs, triggering the attenuation of Nrf2 phosphorylation to weaken Nrf2 translocation into the nucleus in a longer exposure period (more than 5 d). The data in the cells and fish also showed that antioxidant activities were decreased to some extent at 5–7 d for the cells and 7–14 d for the fish. Furthermore, interferon-related factors were decreased in AZ-exposed zebrafish, explaining the reason that fish can't resist the virus infection. Overall, the present study provided a new adverse threat of AZ by amplifying the viral outbreak to endanger ecological safety in aquatic environment.
研究领域:
环境科学
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鱼类病理学
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毒理学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Yuanxing Zhi,Jin Liu,Peihua Kuang,Xin Zhang,Ziwei Xu,Yanshan Chen,Xiuling Lin,Xiaoyan Wu,Pingzheng Zhou,Jianjun Chen
The enzyme cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA and catalyzes the formation of 2′3′-cyclic-GMP-AMP (cGAMP), which in turn triggers interferon (IFN) production. Inappropriate activation of cGAS and production of cGAMP have been linked to a diversity of autoimmune diseases. The volume-regulated anion channels (VRACs) have been recently demonstrated to permeate cGAMP, thus making the channel essential for the activation of the cGAS-cGAMP-STING axis. DCPIB, a prominent inhibitor of VRAC channel, has been recently reported to also significantly activate TREK1 channel. Herein, in this study, we have designed and synthesized a series of novel DCPIB derivatives and investigated their potential regulatory effects on VRAC/TREK1 channels. Our results manifested that compound 6u was a dual inhibitor of VRAC/TREK1 channels with IC 50 s of 7.11 ± 0.94 μM and 4.43 ± 0.90 μM, respectively. On top of that, our data demonstrated that 6u impaired interferon production in a concentration-dependently manner by dampening cGAS-cGAMP-STING pathway without any cytotoxicity when it comes to herpes simplex virus type 1 (HSV1) infection. To sum up, our study not only discovered a novel DCPIB analog with dual inhibitory effects on VRAC/TREK1 channels but also provided a new strategy for the design and development of newly potent VRAC inhibitors, which benefits the treatment of cGAS-STING related autoimmune and inflammatory diseases .
研究领域:
药理学
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免疫学
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分子生物学
·
化学
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产品关联
DOI
PubMed
高影响因子
BIOSENSORS & BIOELECTRONICS
·
2014
·
IF 6.451
Jianfei Xia,Daimin Song,Zonghua Wang,Feifei Zhang,Min Yang,Rijun Gui,Lin Xia,Sai Bi,Yanzhi Xia,Yanhui Li,Linhua Xia
Simultaneous detection of multiple biomarkers holds great promise for acute leukemia evaluation. Here, a novel biosensor is developed for simultaneous electrochemical detection of interferon gamma (IFN-γ) and lysozyme (Lys) based on aptamer recognition by coupling “signal-on” and “signal-off” modes. On one Au electrode, two kinds of signaling probes labeled by the thiolated ferrocene (Fc)- and methy blue (MB)- were designed to hybridize with IFN-γ and Lys aptamers respectively to form partial complementary DNA duplexes. In the presence of IFN-γ and Lys, the target–aptamer interaction led to the release of aptamer from duplex DNA structure . The single-stranded signaling probes thus suffered from the conformation changes, which resulted in the decreased (or increased) oxidation peak current of Fc (or MB) according to the “signal-off (or signal-on)” mode. Electrodes were characterized using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Under the optimized conditions, the signal changes were quantified using square wave voltammetry (SWV). This proposed biosensor for IFN-γ and Lys possessed linear detection range from 0.01 to 10 nM and 0.1 to 100 nM, with the detection limits of 1.14×10 −3 nM and 0.0164 nM, respectively. Moreover, this biosensor was readily regenerated and proved successful toward the practical analysis. The proposed strategy could provide more integrated and reliable information for acute leukemia evaluation.
研究领域:
生物医学工程
·
分析化学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Yijia Yin,Qian Hu,Chenfeng Xu,Qi Qiao,Xianya Qin,Qingle Song,Yang Peng,Yongdan Zhao,Zhiping Zhang
A dual-sensitive nanoparticle delivery system was constructed by incorporating an acid sensitive hydrazone linker into thermosensitive nanoparticles (TSNs) for co-encapsulating doxorubicin (DOX) and interferon γ (IFNγ) and to realize the co-delivery of chemotherapy and immunotherapy agents against melanoma. DOX, a chemotherapeutic drug, was conjugated to TSNs by a pH-sensitive chemical bond, and IFNγ, a potent immune-modulator, was absorbed into TSNs through the thermosensitivity and electrostatics of nanoparticles. Consequently, the dual sensitive drug-loaded TSN delivery systems were successfully built and showed an obvious core–shell structure, good encapsulation efficiency of drugs, sustained and sensitive drug release, prolonged circulation time, as well as excellent synergistic antitumor efficiency against B16F10 tumor bearing mice. Moreover, the combinational antitumor immune responses of hydrazone bearing DOX/IFNγ-TSN (hyd) were strengthened by activating Th1-type CD4+ T cells, cytotoxic T lymphocytes, and natural killer cells, downregulating the expression levels of immunosuppressive cytokines, such as IL10 and TGFβ, and upregulating the secretion of IL2 and TNFα. Taken together, the multifunctional TSNs system provides a promising strategy for multiple drugs co-delivery with distinct properties.
研究领域:
肿瘤学
·
药剂学
·
免疫学
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DOI
PubMed
高影响因子
BIOSENSORS & BIOELECTRONICS
·
2019
·
IF 9.518
Huan Li,Shihao Song,Meiqi Wen,Ting Bao,Zhen Wu,Huayu Xiong,Xiuhua Zhang,Wei Wen,Shengfu Wang
In this paper, a novel label-free electrochemical impedance aptasensor for highly sensitive detection of IFN-γ based on target-induced exonuclease inhibition was constructed. For this purpose, we designed a DNA hairpin modified on the gold electrode whose loop was the aptamer of the IFN-γ, and the stem was 5′-thiol-modified. In the absence of IFN-γ, Exonuclease III (Exo III) and Exonuclease I (Exo I) digested the double-stranded and single-stranded strands of the hairpin DNA, respectively, causing smaller impedance value on the surface of the electrode. In the presence of IFN-γ, the function of Exo III was greatly inhibited by the binding of the aptamer with the target, and it stopped after cutting three bases of the hairpin DNA. Forming a major target-bound aptamer digestion product, it could not be digested by Exo I, so there was larger impedance on the electrode surface . The calibration curve for IFN-γ was linear in the range of 1 pM–50 nM with the detection limit (LOD) of 0.7 pM . The proposed aptasensor proved good selectivity and reproducibility, and low cost. In addition, the biosensor was able to detect IFN-γ in serum samples successfully, which is expected to provide an efficient method for TB diagnosis at early stages.
研究领域:
生物传感技术
·
医学诊断
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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）