Nature Communications
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2025
·Vol. 16
·期 1
·1-16
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IF 15.7
Zhang Qiang,Chen Wanyi,Qin Ming,Wang Yuhao,Pu Zhongji,Ding Keyan,Liu Yuyue,Zhang Qunfeng,Li Dongfang,Li Xinjia,Zhao Yu,Yao Jianhua,Huang Lei,Wu Jianping,Yang Lirong,Chen Huajun,Yu Haoran
Traditional protein engineering methods, such as directed evolution, while effective, are often slow and labor-intensive. Advances in machine learning and automated biofoundry present new opportunities for optimizing these processes. This study devises a protein language model-enabled automatic evolution platform, a closed-loop system for automated protein engineering within the Design-Build-Test-Learn cycle. The protein language model ESM-2 makes zero-shot prediction of 96 variants to initiate the cycle. The biofoundry constructs and evaluates these variants, and feeds the results back to a multi-layer perceptron to train a fitness predictor, which then makes prediction of second round of 96 variants with improved fitness. With the tRNA synthetase as a model enzyme, four-rounds of evolution carried out within 10 days lead to mutants with enzyme activity improved by up to 2.4-fold. Our system significantly enhances the speed and accuracy of protein evolution, driving faster advancements in protein engineering for industrial applications.
研究领域:
生物信息学
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合成生物学
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PubMed
高影响因子
DEVELOPMENTAL CELL
·
2023
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IF 11.8
Sirui Zhu,Yuanyuan Li,You Wu,Yanan Shen,Ying Wang,Yujie Yan,Weijun Chen,Qiong Fu,Yirong Wang,Xiang Yu,Feng Yu
tRNA fragments (tRFs) are a recently identified class of small noncoding RNAs. To date, the regulation of tRF abundance and its functional mechanisms have been largely unclear in plants. We investigated how the Arabidopsis thaliana receptor kinase FERONIA (FER) regulates the abundance of tRFs to inhibit global mRNA translation. We demonstrate that FER regulates tRF abundance by directly phosphorylating the tRNA-binding protein YUELAO (YL) to modulate its function. Downregulation of FER and YL prevented the modification of tRNA via cytosine-5-methylation and 2'-O-methylation, thereby increasing tRF abundance. Furthermore, we show that YL acts as an important genetic downstream target of FER signaling, and knockdown of a specific tRF partially rescues the root hair growth defects of fer and yl mutants. Our findings shed light on the abundance and regulatory mechanisms of tRF and their role in inhibiting translation in plants.
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高影响因子
CELL
·
2024
·
IF 45.5
Zhi Zong,Feng Xie,Shuai Wang,Xiaojin Wu,Zhenyu Zhang,Bing Yang,Fangfang Zhou
Lysine lactylation is a post-translational modification that links cellular metabolism to protein function. Here, we find that AARS1 functions as a lactate sensor that mediates global lysine lacylation in tumor cells. AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue. Proteomics studies reveal a large number of AARS1 targets, including p53 where lysine 120 and lysine 139 in the DNA binding domain are lactylated. Generation and utilization of p53 variants carrying constitutively lactylated lysine residues revealed that AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation. AARS1 expression and p53 lacylation correlate with poor prognosis among cancer patients carrying wild type p53. β-alanine disrupts lactate binding to AARS1, reduces p53 lacylation, and mitigates tumorigenesis in animal models. We propose that AARS1 contributes to tumorigenesis by coupling tumor cell metabolism to proteome alteration.
研究领域:
癌症生物学
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分子生物学
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细胞代谢
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蛋白质组学
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高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Han Lin,Ying Yan,Chenyu Qiu,Junqi Wang,Wenying Fu,Chongchong Shu,Yinghua Chen,Chenxin Xu,Shaotang Li,Yiqun Xia,Jundixia Chen,Yunzhi Chen,Peng Zou,Ri Cui,Daoyong Ni
Glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is a key enzyme in protein synthesis and is implicated in various diseases, including inflammation, fibrosis, and cancer. Here, we found that EPRS1 is highly expressed in patients with colon cancer and is positively correlated with poor prognosis. Halofuginone, a derivative of febrifugine extracted from the traditional Chinese herb Dichroa febrifuga , was previously identified as a specific inhibitor of EPRS1. Our research found that halofuginone significantly inhibit the growth of colon cancer cells. Mechanistic investigations demonstrated that halofuginone treatment activates the ATF4-CHOP and JNK signaling pathways in colon cancer cells. Further research revealed that halofuginone inhibits the expression of NRF2, and that high NRF2 expression can reverse halofuginone's anti-colon cancer activity. Importantly, the inhibition of NRF2, along with the activation of the ATF4-CHOP and JNK signaling pathways caused by halofuginone, can be substantially reversed by proline. Additionally, we observed a synergistic antitumor effect when halofuginone was combined with bortezomib, a well-established proteasome inhibitor, in colon cancer cells. These results imply that the halofuginone-bortezomib combination could offer a promising therapeutic option for colon cancer treatment. In summary, our research comprehensively elucidates the molecular mechanisms underlying halofuginone's action against colon cancer and provides new insights into halofuginone-based combination therapies.
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CELL DEATH AND DIFFERENTIATION
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2024
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IF 13.7
Cai Jiangxue,Li Chenxuan,Liu Suyuan,Tan Meiling,Sun Yiran,Sun Xiaoxiao,Yang Miaoxin,He Bin
The cellular stress response system in immune cells plays a crucial role in regulating the development of inflammatory diseases. In response to cellular damage or microbial infection, the assembly of the NLRP3 inflammasome induces pyroptosis and the release of inflammatory cytokines. Meanwhile, Angiogenin (Ang)-mediated transfer RNA-derived small RNAs (tsRNAs) promote cell survival under stressful conditions. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications in regulating inflammatory diseases remains poorly understood. In this study, it was demonstrated that Ang deficiency exacerbated sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis. Moreover, Ang-induced 5′-tsRNAs inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5′-tsRNAs recruit DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. Furthermore, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, ultimately leading to an exacerbation of NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Altogether, our study sheds a new light on the role of Ang-induced 5′-tsRNAs in regulating NLRP3 inflammasome activation via SGs, and highlights tsRNAs as a promising target for the treatment of NLRP3 inflammasome-related diseases.
研究领域:
免疫学
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分子生物学
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炎症
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代谢紊乱
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PubMed
高影响因子
Biomolecules
·
2023
·Vol. 13
·期 4
·610
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IF 5.5
Zhiyang Hu,Jinming Liang,Taogeng Su,Di Zhang,Hao Li,Xiangdong Gao,Wenbin Yao,Xiaoda Song
In the field of genetic code expansion (GCE), improvements in the efficiency of noncanonical amino acid (ncAA) incorporation have received continuous attention. By analyzing the reported gene sequences of giant virus species, we noticed some sequence differences at the tRNA binding interface. On the basis of the structural and activity differences betweenMethanococcus jannaschiiTyrosyl-tRNA Synthetase (MjTyrRS) andmimivirusTyrosyl-tRNA Synthetase (MVTyrRS), we found that the size of the anticodon-recognized loop of MjTyrRS influences its suppression activity regarding triplet and specific quadruplet codons. Therefore, three MjTyrRS mutants with loop minimization were designed. The suppression of wild-type MjTyrRS loop-minimized mutants increased by 1.8–4.3-fold, and the MjTyrRS variants enhanced the activity of the incorporation of ncAAs by 15–150% through loop minimization. In addition, for specific quadruplet codons, the loop minimization of MjTyrRS also improves the suppression efficiency. These results suggest that loop minimization of MjTyrRS may provide a general strategy for the efficient synthesis of ncAAs-containing proteins.Keywords:genetic code expansion;giant virus;anticodon recognition;loop minimization;noncanonical amino acids
研究领域:
生物化学
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分子生物学
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合成生物学
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高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
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2026
·Vol. 31
·期 1
·33
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IF 12.2
Ding Ying,Feng Ziyang,Chen Guanjun,Liu Yunqing,Zhu Yuxing,Cao Ke
Background Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with rapid progression and poor prognosis. Although N1-methyladenosine (m 1 A) modification has been implicated in cancer development, the specific role of tRNA m 1 A modification in ATC remains unclear. Methods An integrated multi-omics approach is employed, including m 1 A-MAP-tRNA-seq, tRNA-seq, RNA-seq, and Ribo-seq, complemented by functional assays such as tRNA aminoacylation assay, puromycin intake assay, and L-HPG staining. Additional experiments involved polysome profiling qRT-PCR, codon-switch assay, endoplasmic reticulum (ER)-tracker and TPE-MI staining, transmission electron microscopy, ChIP-qPCR, dual-luciferase reporter assay, and BODIPY staining to elucidate the underlying mechanism. Results TRMT6/TRMT61A is significantly upregulated in ATC. The complex promotes tumor cell proliferation and metastasis by enhancing the aminoacylation of specific tRNAs, thereby facilitating global protein translation. Elevated translation led to the accumulation of unfolded proteins in the ER, which activates the IRE1α–XBP1s pathway. Notably, m 1 A modification also increased IRE1α translation, further amplifying the pathway. Activation of the IRE1α–XBP1s pathway upregulates DGAT1 expression, which promotes triglyceride synthesis. Conclusions Together, these findings reveal a previously unrecognized mechanism by which TRMT6/TRMT61A drives ATC progression through translational and metabolic reprogramming, identifying TRMT6/TRMT61A as a promising therapeutic target in ATC. Graphical abstract
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Nature Communications
·
2021
·Vol. 12
·期 1
·1-14
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IF 14.919
Wang Yuqin,Guan Xiaoyu,Zhang Shanyu,Liu Yao,Wang Sha,Fan Pingping,Du Xiaoyu,Yan Shuanghong,Zhang Panke,Chen Hong-Yuan,Li Wenfei,Zhang Daoqiang,Huang Shuo
Folding of RNA can produce elaborate tertiary structures, corresponding to their diverse roles in the regulation of biological activities. Direct observation of RNA structures at high resolution in their native form however remains a challenge. The large vestibule and the narrow constriction of a Mycobacterium smegmatis porin A (MspA) suggests a sensing mode called nanopore trapping/translocation, which clearly distinguishes between microRNA, small interfering RNA (siRNA), transfer RNA (tRNA) and 5 S ribosomal RNA (rRNA). To further profit from the acquired event characteristics, a custom machine learning algorithm is developed. Events from measurements with a mixture of RNA analytes can be automatically classified, reporting a general accuracy of ~93.4%. tRNAs, which possess a unique tertiary structure, report a highly distinguishable sensing feature, different from all other RNA types tested in this study. With this strategy, tRNAs from different sources are measured and a high structural conservation across different species is observed in single molecule.
研究领域:
纳米技术
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生物物理学
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生物信息学
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分子生物学
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PubMed
高影响因子
iScience
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2024
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IF 4.6
Hui Han,Yucong Sun,Wei Wei,Zixin Huang,Maosheng Cheng,Hongshen Qiu,Juan Wang,Siyi Zheng,Lianlian Liu,Qiang Zhang,Canfeng Zhang,Jieyi Ma,Siyao Guo,Zhaoyu Wang,Zhenpeng Li,Xu Jiang,Shuibin Lin,Qianwen Liu,Shuishen Zhang
Summary Emerging studies have demonstrated the link between RNA modifications and various cancers, while the predictive value and functional mechanisms of RNA modification-related genes (RMGs) in esophageal squamous cell carcinoma (ESCC) remain unclear. Here we established a prognostic signature for ESCC based on five RMGs. The analysis of ESCC clinical samples further verified the prognostic power of the prognostic signature. Moreover, we found that the knockdown of NSUN6 promotes ESCC progression in vitro and in vivo , whereas the overexpression of NSUN6 inhibits the malignant phenotype of ESCC cells. Mechanically, NSUN6 mediated tRNA m 5 C modifications selectively enhance the translation efficiency of CDH1 mRNA in a codon dependent manner. Rescue assays revealed that E-cadherin is an essential downstream target that mediates NSUN6’s function in the regulation of ESCC progression. These findings offer additional insights into the link between ESCC and RMGs, as well as provide potential strategies for ESCC management and therapy.
研究领域:
肿瘤学
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分子生物学
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基因组学
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PubMed
高影响因子
CELL
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2023
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IF 64.5
Qinqin Cui,Hongyun Bi,Zhanyun Lv,Qigui Wu,Jianfeng Hua,Bokai Gu,Chanjuan Huo,Mingmin Tang,Yanqin Chen,Chongjiu Chen,Sihan Chen,Xinrui Zhang,Zhangrui Wu,Zhengkai Lao,Nengyin Sheng,Chengyong Shen,Yongdeng Zhang,Zhi-Ying Wu,Zhigang Jin,Peiguo Yang,Huaqing Liu,Jinsong Li,Ge Bai
Summary Complex diseases often involve the interplay between genetic and environmental factors. Charcot-Marie-Tooth type 2 neuropathies (CMT2) are a group of genetically heterogeneous disorders, in which similar peripheral neuropathology is inexplicably caused by various mutated genes. Their possible molecular links remain elusive. Here, we found that upon environmental stress, many CMT2-causing mutant proteins adopt similar properties by entering stress granules (SGs), where they aberrantly interact with G3BP and integrate into SG pathways. For example, glycyl-tRNA synthetase (GlyRS) is translocated from the cytoplasm into SGs upon stress, where the mutant GlyRS perturbs the G3BP-centric SG network by aberrantly binding to G3BP. This disrupts SG-mediated stress responses, leading to increased stress vulnerability in motoneurons. Disrupting this aberrant interaction rescues SG abnormalities and alleviates motor deficits in CMT2D mice. These findings reveal a stress-dependent molecular link across diverse CMT2 mutants and provide a conceptual framework for understanding genetic heterogeneity in light of environmental stress.
研究领域:
神经病学
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分子生物学
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遗传学
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PubMed
高影响因子
Advanced Science
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2024
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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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高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2024
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IF 2.5
Juanjuan Zhu,Wenmin Tang,Xian Wu,Mao Mu,Quan Zhang,Xueke Zhao
Tectorigenin (TEC) as a plant extract has the advantage of low side effects on metabolic dysfunction-associated steatohepatitis (MASH) treatment. Our previous study have shown that tRNA-derived RNA fragments (tRFs) associated with autophagy and pyroptosis in MASH, but whether TEC can mitigate MASH through tRFs-mediated mitophagy is not fully understood. This study aims to investigate whether TEC relies on tRFs to adjust the crosstalk of hepatocyte mitophagy with pyroptosis in MASH. Immunofluorescence results of PINK1 and PRKN with MitoTracker Green-labeled mitochondria verified that TEC enhanced mitophagy. Additionally, TEC inhibited pyroptosis, as reflected by the level of GSDME, NLRP3, IL-1β, and IL-18 decreased after TEC treatment, while the effect of pyroptosis inhibition by TEC was abrogated by Pink1 silencing. We found that the upregulation expression of tRF-3040b caused by MASH was suppressed by TEC. The promotion of mitophagy and the suppression of pyroptosis induced by TEC were abrogated by tRF-3040b mimics. TEC reduced lipid deposition, inflammation, and pyroptosis, and promoted mitophagy in mice, but tRF-3040b agomir inhibited these effects. In summary, our findings provided that TEC significantly reduced the expression of tRF-3040b to enhance mitophagy, thereby inhibiting pyroptosis in MASH. We elucidated a powerful theoretical basis and provided safe and effective potential drugs for MASH with the prevention and treatment.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
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