iScience
·
2024
·
IF 4.6
Shengze Zhang,Chuming Luo,Qiqi Chen,Nina Li,Xinzhong Liao,Jiani Wu,Haolu Zha,Ting Xie,Shaohui Bai,Weijian Tian,Lin Zhu,Xuan Zou,Shisong Fang,Caijun Sun,Ying Jiang,Jianhui Yuan,Yuelong Shu,Nan Wu,Huanle Luo
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is crucial in flavivirus infections, modulating the host immune response through interactions with viral proteins. Despite its importance, the relationship between TRAF6 and Zika virus (ZIKV) remains poorly understood. Our prior proteomics analysis revealed reduced TRAF6 protein levels in ZIKV-infected human trophoblast cells compared to non-infected controls. Subsequent studies in cell models and murine tissues confirmed a significant reduction in both TRAF6 mRNA and protein levels post-ZIKV infection. Further investigations unveiled that ZIKV induces P62-mediated degradation of TRAF6, with NS1 identified as the primary contributor. Co-localization and interaction studies demonstrated that NS1 promotes the association of P62, a key autophagy mediator, with TRAF6. Notably, our findings revealed TRAF6 enhances ZIKV infection, NS1 ubiquitination, NS1 expression, and the production of inflammatory cytokines and chemokines. These insights highlight the intricate TRAF6-ZIKV relationship, offering potential for drug targeting NS1-TRAF6 interactions to manage ZIKV infections effectively.
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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传染病学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2021
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IF 6.953
Min Zou,Jing-Yan Li,Meng-Jia Zhang,Jun-Hui Li,Jun-Tao Huang,Pei-Dan You,Shu-Wen Liu,Chun-Qiong Zhou
At present, there are still no anti-Zika virus (ZIKV) drugs or vaccines approved by FDA with accurate targets and antiviral mechanisms. Considering the RNA G-quadruplex sequences in ZIKV genome, it is very meaningful to develop G-quadruplex binders as potential anti-ZIKV drugs with novel and accurate targets. In this paper, five classical G-quadruplex binders including Ber , Braco 19 , NiL , 360A and PDS have been chosen to discuss their interaction with ZIKV RNA G-quadruplexes. PDS shows higher binding affinity and thermal stability than the other G-quadruplex binders. This property is further evidenced in cells by immunofluorescence microscopy. And PDS shows higher anti-ZIKV activity (EC 50 = 4.2 ± 0.4 μM) than the other G-quadruplex binders as well as the positive control ribavirin, with a low cytotoxicity. By time-of-addition assay, PDS exerts antiviral activity at the post-entry process of ZIKV replication cycle, thus inhibiting ZIKV mRNA replication and protein expression. Furthermore, PDS combines with ZIKV NS2B-NS3 protease and reduces its catalytic activity. This study suggests that G-quadruplex binder PDS is an effective multi-target ZIKV inhibitor, which provides more guidance to design some novel anti-ZIKV drugs targeting ZIKV RNA G-quadruplexes.
研究领域:
病毒学
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药物化学
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分子生物学
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DOI
PubMed
高影响因子
VIROLOGY
·
2023
·
IF 3.7
Xiaoyan Zheng,Ran Wang,Chenghong Yin
Dengue virus (DENV), Japanese encephalitis virus (JEV) and Zika virus (ZIKV) are the three most important flaviviruses, which can cause health problems worldwide. All these flaviviruses can cause liver damage, however, the mechanism of liver injury is still unclear. Metabolomics can give insight into the full complexity of a disease. In our study, we used an LC-MS method to analysis the metabolites in liver samples of the three flaviviruses-infected mice and the non-infected mice. Compared with the control mice, the liver of the DENV-infected, JEV-infected, and ZIKV-infected mice had 32, 34, and 55 differential metabolites. We also found that there were obvious differences in some metabolic pathways among the four groups. Metabonomic analysis of liver is very important for understanding the pathogenesis of flaviviruses.
研究领域:
病毒学
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医学
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代谢组学
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DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2021
·Vol. 297
·期 1
·
IF 5.157
Bochuan Yuan,Ziwei Wu,Wei Ji,Dong Liu,Xiang Guo,Donghui Yang,Aili Fan,Hongli Jia,Ming Ma,Wenhan Lin
The fungal cyclohexadepsipeptides destruxins (DTXs), isaridins (ISDs), and isariins (ISRs) are nonribosomal peptides whose structures include a 19-membered ring composed of five amino acid residues and one α- or β-hydroxy acid residue. These cyclohexadepsipeptides contain unusual nonproteinogenic amino acid–building blocks and possess a range of antiviral, antibacterial, and other activities. The biosynthetic gene clusters for ISDs and ISRs have not been identified, and the biosynthesis of the nonproteinogenic (3S)-methyl-l-proline residue, which is found in DTXs, ISDs, and many other natural products, lacks full characterization. In an ongoing effort to identify compounds that can inhibit the Zika virus (ZIKV), we examined the extract of marine-derived fungus Beauveria felina SX-6-22 and discovered 30 DTXs, ISDs, and ISRs (1–30) including seven new compounds (1–7). The anti-ZIKV assays showed that 9–12 and 16–18 possess inhibitory activities against ZIKV RNA replication and NS5 (nonstructural protein 5) production in ZIKV-infected A549 cells. We sequenced the genome of B. felina SX-6-22 and identified three biosynthetic gene clusters detx, isd and isr, which are responsible for the biosynthesis of DTXs, ISDs, and ISRs, respectively. Comparative analyses of the three gene clusters clarified the biosynthetic relationships among these cyclohexadepsipeptides. Finally, we characterized the entire biosynthesis of nonproteinogenic building block (3S)-methyl-l-proline. The Δ1-pyrroline-5-carboxylate reductases (P5CRs), also used in the biosynthesis of l-proline, were demonstrated to catalyze the final reduction step in (3S)-methyl-l-proline formation, suggesting potential cross talk between primary and secondary metabolisms. These results provide opportunities for biosynthetic pathway engineering to generate new anti-ZIKV cyclohexadepsipeptides.
研究领域:
药理学
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微生物学
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分子生物学
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生物化学
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基因组学
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DOI
PubMed
高影响因子
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