ACTA PHARMACOLOGICA SINICA
·
2024
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IF 6.9
Zhang Chen-chun,Li Yuan,Jiang Chang-you,Le Qiu-min,Liu Xing,Ma Lan,Wang Fei-fei
The O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is a critical post-translational modification that couples the external stimuli to intracellular signal transduction networks. However, the critical protein targets of O-GlcNAcylation in oxidative stress-induced apoptosis remain to be elucidated. Here, we show that treatment with H 2 O 2 inhibited O-GlcNAcylation, impaired cell viability, increased the cleaved caspase 3 and accelerated apoptosis of neuroblastoma N2a cells. The O-GlcNAc transferase (OGT) inhibitor OSMI-1 or the O-GlcNAcase (OGA) inhibitor Thiamet-G enhanced or inhibited H 2 O 2 -induced apoptosis, respectively. The total and phosphorylated protein levels, as well as the promoter activities of signal transducer and activator of transcription factor 3 (STAT3) and Forkhead box protein O 1 (FOXO1) were suppressed by OSMI-1. In contrast, overexpressing OGT or treating with Thiamet-G increased the total protein levels of STAT3 and FOXO1. Overexpression of STAT3 or FOXO1 abolished OSMI-1-induced apoptosis. Whereas the anti-apoptotic effect of OGT and Thiamet-G in H 2 O 2 -treated cells was abolished by either downregulating the expression or activity of endogenous STAT3 or FOXO1. These results suggest that STAT3 or FOXO1 are the potential targets of O-GlcNAcylation involved in the H 2 O 2 -induced apoptosis of N2a cells.
研究领域:
细胞生物学
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分子生物学
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神经科学
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DOI
PubMed
高影响因子
RSC Advances
·
2016
·Vol. 6
·期 92
·89484-89491
·
IF 3.289
Yingshuai Liu,Jin Xie,Zeying Zhang,Zhisong Lu
O-GlcNAcylation is a very important post-translational modification of nucleocytoplasmic proteins. Aberrant O-GlcNacylation has been found in a variety of human diseases including many types of cancers, diabetes, and Alzheimer's disease. However, analysis of protein O-GlcNacylation still remains a great challenge due to its low levels and labile nature. Herein, a highly sensitive and reliable colorimetric method is developed by use of wheat germ agglutinin (WGA) lectin for specific recognition of O-GlcNAc and gold nanoparticle (AuNP)-catalyzed copper deposition for signal amplification. In presence of the target molecule, AuNP is specifically introduced onto the sensing surface and then catalyzes the copper deposition. An Au@Cu core–shell structure is produced from the deposition. The obtained copper shell on AuNP is dissolved by FeCl3 due to the oxidation–reduction reaction between copper and Fe3+, resulting in Cu2+ and Fe2+, which subsequently form a red coordination complex in the presence of bathophenanthrolinedisulfonic acid disodium salt (BPT2−). Thus, the amount of the red complex is proportional to the level of O-GlcNAc. Qualitative O-GlcNAc detection is realized by direct readout with the naked eye, while the quantitative analysis is achieved by measurement of the absorbance using a UV-Vis spectrophotometer. With increasing time, more and more copper is deposited on the surface of AuNP, thus achieving significant signal amplification. Under optimal conditions, an ultralow limit of detection (LOD) down to 0.02 pg mL−1 is achieved with GlcNAc-conjugated BSA as a model analyte. The developed platform was also successfully applied to analyze O-GlcNAcylation levels in prostate cancer cell line PC-3 and normal cell line RWPE-1. The results obtained by the proposed method are in good agreement with the data from protein microarray assays, demonstrating its great potential for sensitive and reliable O-GlcNAcaylation detection in fundamental research and in cancer diagnosis.
研究领域:
生物化学
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分析化学
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癌症生物学
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蛋白质科学
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DOI
高影响因子
MOLECULAR CELL
·
2023
·
IF 16
Chenchen Xu,Xiaoqing Pan,Dong Wang,Yuanyuan Guan,Wenyu Yang,Xing Chen,Ying Liu
The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.
研究领域:
细胞生物学
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分子生物学
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代谢
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信号通路
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DOI
PubMed
高影响因子
International Journal of Oral Science
·
2026
·Vol. 18
·期 1
·32
·
IF 17.6
Zhang Zhongyin,Shan Zerui,Chen Xinyu,Xia Yu,Meng Li,Zhang Yuxin,Wu Caihong,Yuan Lichan,Ma Junqing
Post-translational modifications (PTMs) have been gradually elucidated in congenital malformations such as cleft palate. Among them, O-GlcNAcylation as a dynamic PTM of proteins regulates various critical biological processes including transcription, translation, and cell fate determination. In this study, a substantial decline in O-linked β-D-N-acetylglucosamine (O-GlcNAc) levels was detected within the palatine plates of all-trans retinoic acid (atRA)-induced cleft palate mice. The role of O-GlcNAc transferase (OGT), the sole enzyme responsible for catalyzing O-GlcNAcylation, was investigated in the process of palatal development. In a zebrafish model, the loss of O-GlcNAc resulted in an elevated prevalence of cleft palate and compromised palatal bone formation. Mechanistically, O-GlcNAcylation of myeloid ecotropic viral integration site 2 (MEIS2), which is mediated by OGT, was found to maintain osteogenic homeostasis by modulating its protein stability through inhibition of ubiquitination. Notably, the serine 237 residue (Ser237) was identified as a critical site for MEIS2 O-GlcNAcylation. Together, the present study uncovers the important function of MEIS2 O-GlcNAcylation in palatal bone development and establishes a novel theoretical framework for understanding the regulatory network of palatal development. This finding may provide novel avenues for the future diagnosis and prevention of cleft palate.
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PubMed
高影响因子
Cell Reports
·
2021
·
IF 9.423
Tanjing Song,Qingli Zou,Yingying Yan,Suli Lv,Neng Li,Xuefeng Zhao,Xianyun Ma,Haigang Liu,Borui Tang,Lidong Sun
Summary Histone lysine methylation functions at the interface of the extracellular environment and intracellular gene expression. DOT1L is a versatile histone H3K79 methyltransferase with a prominent role in MLL-fusion leukemia, yet little is known about how DOT1L responds to extracellular stimuli. Here, we report that DOT1L protein stability is regulated by the extracellular glucose level through the hexosamine biosynthetic pathway (HBP). Mechanistically, DOT1L is O-GlcNAcylated at evolutionarily conserved S1511 in its C terminus. We identify UBE3C as a DOT1L E3 ubiquitin ligase promoting DOT1L degradation whose interaction with DOT1L is susceptible to O-GlcNAcylation. Consequently, HBP enhances H3K79 methylation and expression of critical DOT1L target genes such as HOXA9/MEIS1, promoting cell proliferation in MLL-fusion leukemia. Inhibiting HBP or O-GlcNAc transferase (OGT) increases cellular sensitivity to DOT1L inhibitor. Overall, our work uncovers O-GlcNAcylation and UBE3C as critical determinants of DOT1L protein abundance, revealing a mechanism by which glucose metabolism affects malignancy progression through histone methylation.
研究领域:
癌症生物学
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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
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 23
·e70940
·
IF 4.2
Hao Tan,Cao Fang,Yiyun Tan,Zhi Wang,Yun Zhou,Xing Li
Astragalus polysaccharides (APS) are a crucial bioactive component known for their various pharmacological properties. Abnormal O‐linked β‐N‐acetylglucosamine modification (O‐GlcNAcylation) is noted in cases of intervertebral disc degeneration (IVDD). Nonetheless, it remains uncertain whether APS regulates the process of O‐GlcNAcylation associated with IVDD. We employed molecular docking, cycloheximide chase assay, immunohistochemistry, and immunoprecipitation to investigate APS‐mediated OGT/O‐GlcNAcylation regulation of Nrf2. The effects of APS and its role in promoting the O‐GlcNAcylation of Nrf2 in IVDD through both in vivo and in vitro studies are discussed. In vitro investigations demonstrated an increase in the levels of OGT and O‐GlcNAcylation in nucleus pulposus cells (NPCs) following exposure to tert‐butyl hydroperoxide (TBHP). APS further facilitated improvements in OGT expression and O‐GlcNAcylation processes, restoring the viability of NPCs inhibited by TBHP and promoting the synthesis of collagen II and aggrecan, while reducing apoptosis. Mechanistically, APS promotes the expression of OGT by targeting it. Furthermore, O‐GlcNAcylation mediated by OGT stabilizes the expression of Nrf2 via the ubiquitin‐proteasome pathway. Rescue experiments indicated that the disruption of either OGT or Nrf2 expression negated the protective role of APS on NPCs. Ultimately, both in vitro and in vivo studies indicated that APS significantly enhanced OGT expression and O‐GlcNAcylation, which subsequently improved Nrf2 expression and contributed to the alleviation of IVDD in rats. APS promotes O‐GlcNAcylation through OGT, thereby stabilizing the expression of Nrf2, which in turn contributes to the improvement of IVDD.
研究领域:
药理学
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分子生物学
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骨科学
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细胞生物学
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天然产物研究
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2019
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IF 3.571
Linhui Qin,Jianping Wang,RongRong Zhao,Xiao Zhang,Yingwu Mei
Ginsenoside-Rb1 (Rb1), a major active component of ginseng, has many benefits for cardiovascular disease and diabetes mellitus (DM), but the effect and mechanism on diabetic cardiomyopathy are not clear. In the present study, we found that Rb1-feeding significantly improved cardiac dysfunction and abnormal cardiomyocytes calcium signaling caused by diabetes. This improved calcium signaling was because Rb1 reduced Ca2+ leakage caused by overactivated ryanodine receptor 2 (RyR2) and increased Ca2+ uptake by sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA 2a). Furthermore, we found that Rb1 not only enhanced energy metabolism like metformin and eliminated O-GlcNAcylation of calcium handling proteins to regulate calcium signaling but also directly inhibited RyR2 activity to regulate calcium signaling. The present study indicated that as a health supplement or drug, Rb1 was a relatively effective auxiliary therapeutic substance for diabetic cardiomyopathy.
研究领域:
药理学
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心脏病学
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糖尿病
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分子生物学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
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IF 13.3
Haiyang Wang,Hao Zhuang,Chunyan Wu,Bangting Wang,Shijie Zhang,Yao Wang,Li Liu,Lianzhen Yu,Lei Zhang,Su Jing,Zhining Fan
The limited treatment options for colorectal cancer (CRC) and its adverse effects of chemotherapy underscore the urgent need for innovative therapeutic strategies. Focusing on early cellular glycosylation, particularly through the targeting of O-GlcNAcylation with small-molecule inhibitors, emerges as a promising direction. In this study, we developed artificial cell-like nanovesicles with a bilayer membrane structure to encapsulate OSMI-1, a specific inhibitor of O-GlcNAc transferase, aimed at inhibiting CRC progression. To enhance the effectiveness and specificity of the treatment, these self-targeted nanovesicles (T–Se–Lip–OSMI) were reinforced using internal diselenide bridges enabling redox-responsive release within the tumor microenvironment. In vitro assays revealed that T–Se–Lip–OSMI substantially diminished CRC cell proliferation, migration, and invasion. This was further validated using patient-derived organoid models, which highlighted the superior therapeutic efficacy of T–Se–Lip–OSMI over nanovesicles without the diselenide bridge. Subsequent in vivo studies confirmed its targeted delivery and pronounced suppression of tumor growth. Further mechanistic analysis illustrated that the therapeutic effect was mediated through the inhibition of O-GlcNAcylation of the Yes-associated protein (YAP), ultimately preventing the nuclear translocation of YAP and the activation of oncogenic downstream targets. This study leverages the unique properties of the diselenide bridge to enhance stability and functionality of the nanovesicles, offering a novel avenue for targeted CRC treatment.
研究领域:
癌症生物学
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药学
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分子生物学
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纳米技术
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细胞生物学
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DOI
高影响因子
Communications Biology
·
2026
·
IF 5.8
Gu Xunhu,Liu Xu,Xiong Yong,Chen Xuefen,Zhang Yancai,Zheng Li-Li,Wang Wei
Major depressive disorder is associated with impaired excitatory synaptic transmission, but the molecular mechanisms linking chronic stress to altered AMPA receptor trafficking remain incompletely understood. Here we show that chronic mild stress increases OGT-mediated O-GlcNAcylation of PIN at serine 88, which stabilizes PIN and enhances its interaction with nitric oxide synthase. This suppresses nitric oxide synthase activity, reduces stargazin S-nitrosylation, weakens stargazin-GluA1 binding, and impairs GluA1-containing AMPA receptor trafficking. Genetic or pharmacological inhibition of OGT restores this signaling pathway and alleviates stress-induced depression-like behaviors in mice. These findings identify the OGT-PIN-NOS-stargazin axis as a regulator of stress-induced synaptic dysfunction and suggest that targeting OGT may help restore AMPA receptor trafficking in depression-related conditions.
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DOI
PubMed
高影响因子
ACS Central Science
·
2024
·
IF 12.7
Xiangfeng Meng,Yue Zhou,Lei Xu,Limu Hu,Changjiang Wang,Xiao Tian,Xiang Zhang,Yi Hao,Bo Cheng,Jing Ma,Lei Wang,Jialin Liu,Ran Xie
Glycosylation plays a pivotal role in the intricate landscape of human cholangiocarcinoma (CCA), actively participating in key pathophysiological processes driving tumor progression. Among the various glycosylation modifications, O-linked β-N-acetyl-glucosamine modification (O-GlcNAcylation) emerges as a dynamic regulator influencing diverse tumor-associated biological activities. In this study, we employed a state-of-the-art chemical proteomic approach to analyze intact glycopeptides, unveiling the critical role of O-GlcNAcylation in orchestrating Keratin 18 (K18) and its interplay with tricarboxylic acid (TCA) cycle enzymes, specifically isocitrate dehydrogenases (IDHs), to propel CCA progression. Our findings shed light on the mechanistic intricacies of O-GlcNAcylation, revealing that site-specific modification of K18 on Ser 30 serves as a stabilizing factor, amplifying the expression of cell cycle checkpoints. This molecular event intricately fosters cell cycle progression and augments cellular growth in CCA. Notably, the interaction between O-GlcNAcylated K18 and IDHs orchestrates metabolic reprogramming by down-regulating citrate and isocitrate levels while elevating α-ketoglutarate (α-KG). These metabolic shifts further contribute to the overall tumorigenic potential of CCA. Our study thus expands the current understanding of protein O-GlcNAcylation and introduces a new layer of complexity to post-translational control over metabolism and tumorigenesis.
研究领域:
癌症生物学
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分子生物学
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生物化学
·
细胞生物学
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代谢学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2026
·
IF 2.5
Sicheng Fu,Chunju Yang,Zhiping Liang,Lin Zhong,Shufeng Ji,Yuanxiang Wang,Junjian Wang,Zhanfang Kang,Junguo Bu,Hong Wang
Metastasis is the leading cause of treatment failure and poor prognosis in triple-negative breast cancer (TNBC), underscoring the urgent need for effective therapeutic strategies. In this study, we show that O-GlcNAcylation catalyzed by O-GlcNAc transferase (OGT) increases NSD2 stability and thereby promotes TNBC metastasis. Mechanistically, OGT directly interacts with NSD2 and facilitates its O-GlcNAcylation, which impedes ubiquitin-mediated degradation and enhances NSD2 protein stability. OGT knockdown reduces NSD2 protein levels, downregulates extracellular matrix (ECM)-related signaling pathways, decreases collagen production and cell–matrix adhesion, and ultimately inhibits TNBC cell invasion and tumor metastasis. Importantly, disruption of the OGT–NSD2 axis markedly suppresses metastasis in TNBC xenograft models. Together, these findings reveal a novel mechanism by which OGT drives tumor metastasis through modulation of NSD2 O-GlcNAcylation, and identify the OGT–NSD2 axis as a potential therapeutic target for advanced TNBC.
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DOI
PubMed
高影响因子
Science Bulletin
·
2026
·
IF 20.7
Dan Zhou,Dingru Li,Caimei Zhong,Qiang Li,Peixian Chen,Shuqing Yang,Herong Liang,Zhiyan Chen,Han He,Hua Zhang,Xiaohong Zeng,Mo Chen,Yingxin Lin,Meng Xu,Xingyin Liu,Mengyun Cai,Yuhua Deng
The gut microbiome is increasingly linked to breast cancer (BC) progression; however, specific microbial metabolites and their direct mechanistic connections to oncogenic signalling remain poorly defined. Here, using multi-omics analyses in treatment-naïve patients with BC, we identified gut microbiota-derived uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) as a circulating oncometabolite associated with therapeutic response. We further showed that Ruminococcus lactaris is a key intestinal commensal capable of de novo UDP-GlcNAc biosynthesis, and that microbial-derived UDP-GlcNAc acts as an independent tumour-promoting metabolite, even though the host hexosamine pathways generate the majority of circulating UDP-GlcNAc pools. Mechanistically, UDP-GlcNAc systemically activates O-GlcNAc transferase (OGT), stabilizing the transcription factor NFIB, and triggers a feed-forward loop that upregulates OGT and the proto-oncogene KIT , thereby driving BC progression. Genetic or pharmacological inhibition of OGT disrupts this signaling axis and suppresses tumour growth, even in the presence of UDP-GlcNAc–producing bacteria. These findings reveal a gut microbiota–metabolite–host signalling circuit, in which a microbial metabolite hijacks a core host post-translational modification pathway to promote BC progression, providing novel opportunities for microbiome-targeted diagnosis and therapy. Gut‑microbiota‑derived UDP‑GlcNAc enters circulation, activates host OGT‑mediated O‑GlcNAcylation to stabilize NFIB. This triggers a feed‑forward loop elevating OGT and proto‑oncogene KIT , driving breast tumor progression. Inhibiting OGT blocks this oncogenic axis even with UDP‑GlcNAc‑producing Ruminococcus lactaris . This reveals a gut‑microbe‑metabolite‑host signaling circuit for breast cancer. Download: Download high-res image (170KB) Download: Download full-size image
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高影响因子
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