Antibiotics-Basel
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2025
·Vol. 14
·期 8
·799
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IF 4.6
Sijin Hang,Li Wang,Zhe Ji,Xuqing Shen,Xinyu Fang,Wanqian Li,Yuanying Jiang,Hui Lu
Background/Objectives: The diminished efficacy of azoles in treating fungal infections is attributed to the emergence of resistance among pathogenic fungi. Employing a synergistic approach with other compounds to enhance the antifungal activity of azoles has shown promise, yet the availability of clinically valuable adjuvants for azoles and allylamines remains limited. Studies have demonstrated that the human host environment provides multiple carbon sources, which can influence the susceptibility ofC. albicansto antifungal agents. Therefore, a comprehensive investigation into the mechanisms by which carbon sources modulate the susceptibility ofC. albicansto azoles may uncover a novel pathway for enhancing the antifungal efficacy of azoles. Methods: This study explored the impact of various carbon sources on the antifungal efficacy of azoles through methodologies including minimum inhibitory concentration (MIC) assessments, super-MIC growth (SMG) assays, disk diffusion tests, and spot assays. Additionally, the mechanism by which galactose augments the antifungal activity of azoles was investigated using a range of experimental approaches, such as gene knockout and overexpression techniques, quantitative real-time PCR (qRT-PCR), Western blot analysis, and cycloheximide (CHX) chase experiments. Results: This study observed that galactose enhances the efficacy of azoles againstC. albicansby inhibiting the translation of Erg1. This results in the suppression of Erg1 protein levels and subsequent inhibition of ergosterol biosynthesis inC. albicans. Conclusions: InC. albicans, the translation of Erg1 is inhibited when galactose is utilized as a carbon source instead of glucose. This novel discovery of galactose’s inhibitory effect on Erg1 translation is expected to enhance the antifungal efficacy of azoles.
研究领域:
微生物学
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分子生物学
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药理学
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真菌学
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感染性疾病
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Dingyuan Guo,Nan Li,Xiaoyan Zhang,Runxin Zhou,Jie He,Xiao-Ping Ding,Weixing Yu,Fuqiang Tong,Sibi Yin,Yu Wang,Xin Xu,Long Wang,Mingzhu Fan,Shan Feng,Ke Liu,Ke Tang,Zhuqing Ouyang,Yusong R Guo,Yugang Wang
N 6 -acetyl- L - lysine residue is abundant in dietary protein but little is known about its potential influences on the diet-consumers. Herein, it is reported that Lysyl-tRNA synthetase (KARS) mediates co-translational deposition of diet-derived N 6 -acetyl- L -lysine (AcK) in nascent proteins to contribute to the acetylome in cells. Acetylated dietary protein is a direct source of AcK that can widely and substantially regulate the acetylome in multiple organs of mice. By analyzing the mechanisms underlying AcK contributing to the acetylome in mammalian cells, it is found that KARS can utilize AcK as an alternative substrate to produce N 6 -acetyl- l -lysyl-tRNA. The crystal structure of KARS in complex with AcK at 2.26 Å resolution shows that AcK shares the same substrate-binding pocket as L -lysine, allowed by a sidechain flip of Tyr499. The generated N 6 -acetyl- L -lysyl-tRNA introduces AcK into growing nascent polypeptide and results in protein acetylation, including the regions buried inside folded proteins that are post-translational modification (PTM)-inaccessible and functionally important. This undocumented protein modification mechanism is inherently different from PTM and termed as co-translational modification (coTM). It is expected to extend the repertoire of acetylome and improve the understanding of protein modification mechanisms in cells.
研究领域:
分子生物学
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蛋白质组学
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细胞生物学
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营养科学
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产品关联
DOI
PubMed
高影响因子
Clinical and Translational Medicine
·
2025
·Vol. 15
·期 4
·e70286
·
IF 6.8
Kang Li,Yuxuan Yi,Rongsong Ling,Caihua Zhang,Zhihui Zhang,Yue Wang,Ganping Wang,Jie Chen,Maosheng Cheng,Shuang Chen
Oesophageal squamous cell carcinoma (OSCC) represents a highly aggressive malignancy with limited therapeutic options and poor prognosis. This study uncovers PCIF1 as a critical driver of OSCC progression via m6Am RNA modification, leading to translational repression of the tumour suppressor MTF2. Our results demonstrate that PCIF1 selectively suppresses MTF2 translation, activating oncogenic pathways that promote OSCC growth. In vitro and in vivo models confirm that PCIF1 knockdown reduces OSCC progression, whereas MTF2 knockdown counteracts this effect, highlighting the importance of the PCIF1-MTF2 axis. Clinical analyses further reveal that high PCIF1 expression and low MTF2 expression correlate with advanced tumour stage, poor treatment response and decreased overall survival. Furthermore, in a preclinical mouse model, PCIF1 knockout enhanced the efficacy of anti-PD1 immunotherapy, reducing tumour burden and improving histological outcomes. Notably, flow cytometry analysis indicated that PCIF1 primarily exerts its effects through tumour-intrinsic mechanisms rather than direct modulation of the immune microenvironment, distinguishing its mode of action from PD1 blockade. These findings establish PCIF1 and MTF2 as promising prognostic markers and therapeutic targets for OSCC, offering new avenues for treatment strategies and patient stratification. Key points PCIF1 promotes OSCC progression via m6Am methylation at the MTF2 mRNA 5′ cap. m6Am methylation suppresses MTF2 translation, enhancing tumour cell proliferation and invasion. Targeting PCIF1 holds therapeutic potential for OSCC treatment.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
PLoS Pathogens
·
2022
·Vol. 18
·期 9
·e1010808
·
IF 7.464
Pan-Pan Hong,Cang Li,Guo-Juan Niu,Xiao-Fan Zhao,Jin-Xing Wang
Previous studies have shown that the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has antiviral functions or is beneficial for viral replication, however, the detail mechanisms by which mTORC1 enhances viral infection remain unclear. Here, we found that proliferation of white spot syndrome virus (WSSV) was decreased after knockdown of mTor (mechanistic target of rapamycin) or injection inhibitor of mTORC1, rapamycin, in Marsupenaeus japonicus , which suggests that mTORC1 is utilized by WSSV for its replication in shrimp. Mechanistically, WSSV infects shrimp by binding to its receptor, polymeric immunoglobulin receptor (pIgR), and induces the interaction of its intracellular domain with Calmodulin. Calmodulin then promotes the activation of protein kinase B (AKT) by interaction with the pleckstrin homology (PH) domain of AKT. Activated AKT phosphorylates mTOR and results in the activation of the mTORC1 signaling pathway to promote its downstream effectors, ribosomal protein S6 kinase (S6Ks), for viral protein translation. Moreover, mTORC1 also phosphorylates eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which will result in the separation of 4EBP1 from eukaryotic translation initiation factor 4E (eIF4E) for the translation of viral proteins in shrimp. Our data revealed a novel pathway for WSSV proliferation in shrimp and indicated that mTORC1 may represent a potential clinical target for WSSV control in shrimp aquaculture.
White spot syndrome virus (WSSV) is the causative pathogen of white spot disease (WSD) and represents the most destructive viral disease of shrimp. The virus has evolved various strategies to escape from host defenses or exploit host biological pathways for its reproduction. Studies on viral immune-escape mechanisms can provide new strategies for disease prevention and control in shrimp aquaculture. Mechanistic target of rapamycin (mTOR) plays a central role in the regulation of cell growth and metabolism, which nucleates two distinct protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) with diverse functions at different levels of the signaling pathway. mTORC1 is reported to be exploited by viruses in their reproduction. However, the detail mechanism remains unclear. In this study, we identified a new mechanism of mTOR being hijacked by WSSV in shrimp ( Marsupenaeus japonicus ). WSSV infects shrimp by its receptor, pIgR and induces the interaction of the intracellular domain of pIgR with Calmodulin. Calmodulin subsequently promotes the activation of AKT by interaction with the pleckstrin homology domain of the kinase. Activated AKT phosphorylates mTOR and results in the activation of the mTORC1 signaling pathway to promote its downstream effectors, S6Ks, for viral protein synthesis. Moreover, mTORC1 also phosphorylates 4EBP1, which results in the separation of 4EBP1 from eIF4E for the translation of viral proteins in shrimp. Our study reveals a novel strategy for WSSV proliferation in shrimp and indicates that the components of mTORC1 may represent potential clinical targets for WSSV control in shrimp aquaculture.
研究领域:
水产养殖
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病毒学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Sibo Wang,Zhaowen Jiang,Ruixue Chen,Jingbin Duan,Jingsong Guo,Jianing Li,Liang Yang,Xiaoxia Wu,Wei Ji
The translationally controlled tumor protein (TCTP) represents a multifunctional and evolutionarily conserved protein family in eukaryotes. Despite its biological significance, the genetic characteristics and stress-responsive mechanisms of TCTP remain uncharacterized in soybean. This study identifies GmTCTP2 as a drought-responsive gene showing transcriptional upregulation under PEG-induced dehydration and multiple abiotic stresses. Through comprehensive interaction assays including GST pull-down, co-immunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC), we demonstrate that GmTCTP2 physically interacts with the SUMO E2 conjugate enzyme GmSCEc. This interaction enables GmTCTP2 SUMOylation at lysine residues 101 and 167, significantly enhancing its protein stability under drought conditions. Phenotypic analysis revealed that the Arabidopsis TCTP mutant Attctp displays drought-sensitive characteristics, which could be fully complemented by wild-type GmTCTP2 but not by its SUMOylation-deficient variant GmTCTP2 K101 , 167R . Transgenic Arabidopsis overexpressing GmTCTP2 exhibited substantially improved drought tolerance through enhanced photosynthetic efficiency, ROS scavenging capacity, and hormonal signaling modulation, as evidenced by physiological assessments and transcriptomic profiling. Our findings establish that GmSCEc-mediated SUMOylation of GmTCTP2 critically contributes to drought stress adaptation, providing both mechanistic insights into TCTP regulation and valuable genetic resources for engineering drought-resistant crops.
研究领域:
植物学
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分子遗传学
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产品关联
DOI
PubMed
高影响因子
BMC PLANT BIOLOGY
·
2025
·Vol. 25
·期 1
·1-17
·
IF 4.8
Deng Dehai,Qin Yichao,Lin Xiuying,Chu Meng,Lv Daizhu,Lin Huan
Background The oil palm ( Elaeis guineensis ) is a crucial agricultural commodity, yielding the highest oil output among oil-bearing crops. Despite its significance, productivity challenges persist due to genetic and environmental factors. This study breaks new ground by mapping tRNA modifications in oil palm, exploring their roles during fruit ripening, an area not extensively studied in non-model crops. Results Utilizing advanced RNA mass spectrometry techniques, we identified 48 distinct tRNA modifications across 88 sites, alongside 164 genes associated with tRNA modifying enzymes. This comprehensive mapping reveals the decreasing nature of most tRNA modifications during fruit development, except for adenosine 2’-O methylation (Am). It hints at a gradual weakening of protein translation quality control and highlights a unique role for Am during fruit ripening. Additionally, lipidomic analysis tracked 674 lipids in oil palm fruits, indicating a correlation between tRNA modifications and the accumulation of specific lipids. Conclusions This study mapped tRNA modifications in oil palm for the first time and showed the diversity of dynamic changes in tRNA modifications as the fruits develop.
研究领域:
植物学
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分子生物学
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农业科学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2025
·
IF 3.3
Keke Shang,Yang Chen,Jingjie Jin,Tong Wang,Gong Zhang
Genome instability, a hallmark of cancer, leads to endless mutations that eventually cause drug resistance against almost all chemotherapy drugs. This poses a significant obstacle to the success of cancer treatments. Here, we report that aurintricarboxylic acid (ATCA) effectively suppresses the malignant phenotypes, including proliferation, migration, invasion, and clone formation, of cancer cells of multiple cancers, including cisplatin-resistant lung cancer cells, paclitaxel-resistant lung cancer cells, and doxorubicin-resistant breast cancer cells. Interestingly, ATCA does not cause acute cytotoxicity. Proteome analysis of the whole proteome and nascent chains showed that ATCA reduced translation initiation and thus reduced the abundance of the highly abundant respiratory chain complex. This lowered the potential of the mitochondrial membrane and thus restricted the energy production. This principle could be hardly circumvented by cancer cells and thus may serve as a promising and universal candidate for a second-line therapeutic agent to control cancer progression after drug resistance.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 15
·3245
·
IF 4.6
Kai Liu,Yuanyu Huang,Thomas Huang,Pengyuan Yang,Jilie Kong,Huali Shen,Quanqing Zhang
Over the past decade, the number and diversity of identified protein post-translational modifications (PTMs) have grown significantly. However, most PTMs occur at relatively low abundance, making selective enrichment of modified peptides essential. To address this, we developed a thermodynamic model describing the free beads enrichment in suspension enrichment process and derived a theoretical relationship between material dosage and analyte recovery. The model predicts a non-linear trend, with enrichment efficiency increasing up to an optimal dosage and declining thereafter—a pattern confirmed by experimental data. We validated the model using centrifugation-based enrichment for glycosylated peptides and magnetic-based enrichment for phosphorylated peptides. In both cases, the results aligned with theoretical predictions. Additionally, the optimal dosage varied among peptides with the same modification type, highlighting the importance of tailoring enrichment strategies. This study provides a solid theoretical and experimental basis for optimizing PTMs enrichment and advancing more sensitive, accurate, and efficient mass spectrometry-based proteomic workflows.
研究领域:
蛋白质组学
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分子生物学
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生物化学
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分析化学
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结构生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Ginseng Research
·
2019
·
IF 4.029
Qiang Zhao,Yunpeng Bai,Dan Liu,Nan Zhao,Huiyuan Gao,Xiaozhe Zhang
Background Peptides have diverse and important physiological roles in plants and are ideal markers for species identification. It is unclear whether there are specific peptides in Panax quinquefolius L. (PQ). The aims of this study were to identify Quinetides, a series of diverse posttranslational modified native peptides of the ribonuclease-like storage protein (ginseng major protein), from PQ to explore novel peptide markers and develop a new method to distinguish PQ from Panax ginseng. Methods We used different fragmentation modes in the LTQ Orbitrap analysis to identify the enriched Quinetide targets of PQ, and we discovered Quinetide markers of PQ and P. ginseng using ultrahigh-performance liquid chromatography–quadrupole time-of-flight mass spectrometry analysis. These “peptide markers” were validated by simultaneously monitoring Rf and F11 as standard ginsenosides. Results We discovered 100 Quinetides of PQ with various post-translational modifications (PTMs), including a series of glycopeptides, all of which originated from the protein ginseng major protein. We effectively distinguished PQ from P. ginseng using new “peptide markers.” Four unique peptides (Quinetides TP6 and TP7 as markers of PQ and Quinetides TP8 and TP9 as markers of P. ginseng ) and their associated glycosylation products were discovered in PQ and P. ginseng . Conclusion We provide specific information on PQ peptides and propose the clinical application of peptide markers to distinguish PQ from P. ginseng .
研究领域:
植物学
·
药理学
·
分析化学
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DOI
高影响因子
JOURNAL OF BIOTECHNOLOGY
·
2018
·
IF 2.533
Ming Zhao,Shui-Ling Wang,Xin-Yi Tao,Guo-Ling Zhao,Yu-Hong Ren,Feng-Qing Wang,Dong-Zhi Wei
Due to the lack of powerful gene regulation elements, the engineering development of Streptomyces is often limited. Here, we disclosed that the heterologous σ 70 -dependent promoters, which have been reported as inefficient tools for gene expression in Streptomyces , could be efficiently recognized by Streptomyces housekeeping factor σ hrdB . Therefore, an effective strategy was developed to engineer these promoters for robust gene expression in Streptomyces by fusing them with optimized 5′-untranslation regions (5′-UTRs). As a proof of concept, the widely used P tac in E. coli was engineered by fusing its core promoter region with the 5′-UTR R15 from a relatively powerful Streptomyces promoter P kasO * R15 and resulted in P tac* , the activity of which was 8.1-fold that of P tac and 1.7-fold that of P kasO * R15 in S. lividans TK24. Next, the 5′-UTR R15 was optimized by randomizing the ribosome binding site (RBS). Based on the base biases of those RBSs with higher activity, eight artificial RBSs were rationally designed, and the optimal resulting promoter P tac * RBS3 showed about 2.1, 3.6, and 17.6 times the activity of P tac *, P kasO * R15 , and P tac , respectively, demonstrating that the heterologous P tac was converted into a type of robust Streptomyces promoters. This study thus greatly expands promoter diversity for the engineering of Streptomyces .
研究领域:
合成生物学
·
分子遗传学
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产品关联
DOI
PubMed
高影响因子
aBIOTECH
·
2025
·
IF 5
Zhang Wenyang,Wang Yanjiao,Li Wenyan,Wu Shaowen,Chen Yuanyuan,Ye Mingyang,Huang Wenjie,Fernie Alisdair R.,Yan Shijuan
Protein post-translational modifications such as phosphorylation and S -nitrosylation regulate protein functions and cellular programs in eukaryotes. Moreover, extensive evidence suggests crosstalk between these modifications. However, we lack a comprehensive method for the simultaneous detection and analysis of multiple post-translational modifications. Here, we present an optimized workflow that identifies phosphorylation and S -nitrosylation sites using a novel phosphate affinity tag switch technique. Validation with model proteins and complex biological samples confirmed the high sensitivity, coverage, and reproducibility of this method. Applying this method to Arabidopsis thaliana seedlings revealed 12,552 phosphorylation sites and 6,108 S -nitrosylation sites, representing the largest single-study dataset of S -nitrosylation sites to date. This approach enhances our understanding of post-translational modification dynamics in plant signaling, stress responses, and metabolism.
研究领域:
植物生物学
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生物化学
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分子生物学
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蛋白质组学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2025
·
IF 12
Jingjing Zhang,Chao Li,Yuheng Liu,Rui Liao,Dian He,Lifeng Xu,Tingting Chen,Qin Xiao,Mingxing Luo,Yang Chen,Yali Li,Huaxing Zhu,Joseph Rosenecker,Xiaoyan Ding,Shuchen Pei,Shan Guan
The development of mucosal mRNA vaccines is promising but extremely challenging. Major efforts have been focused on optimizing delivery systems, whereas it is still unknown whether the intrinsic quality of mRNA components significantly impacts the potency of airway inoculated mRNA vaccines. Here, we systematically demonstrate mucosal mRNA vaccine requires higher standards of purification and tailor-designed sequence to fulfil its potency compared to parenteral-route inoculated counterpart. Double-stranded RNA (dsRNA) contaminants are prone to trigger innate immune response in the airway that activates the mRNA degradation mechanism, thereby diminishing the mRNA expression and subsequent antigen-specific immune responses. To address these challenges, we developed a strategy that combines optimized untranslated regions (UTRs) screened from endogenous genes of pulmonary cells with affinity chromatography-based purification which effectively removed dsRNA contaminants. The optimized mRNA administered via airway route not only demonstrated superior protein expression (30-fold increase) and reduced inflammation in the lung, but also promoted robust immunity comprising significantly elevated systemic, cellular, and mucosal immune responses, which was in stark contrast to intramuscular injected counterpart that displays less pronounced benefits. Our findings offer new insights into the development of mucosal mRNA therapeutics from an overlooked but crucial perspective of optimizing mRNA components.
研究领域:
免疫学
·
分子生物学
·
疫苗开发
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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）