Glycobiology最新文献

Galectin-3 disrupts tight junctions of airway epithelial cell monolayers by inducing expression and release of matrix metalloproteinases upon influenza a infection. 在感染甲型流感时，Galectin-3 通过诱导基质金属蛋白酶的表达和释放，破坏气道上皮细胞单层的紧密连接。

IF 3.4 3区生物学

Glycobiology Pub Date : 2024-11-21 DOI: 10.1093/glycob/cwae093

Muddassar Iqbal, Chiguang Feng, Guanghui Zong, Lai-Xi Wang, Gerardo R Vasta

{"title":"Galectin-3 disrupts tight junctions of airway epithelial cell monolayers by inducing expression and release of matrix metalloproteinases upon influenza a infection.","authors":"Muddassar Iqbal, Chiguang Feng, Guanghui Zong, Lai-Xi Wang, Gerardo R Vasta","doi":"10.1093/glycob/cwae093","DOIUrl":"https://doi.org/10.1093/glycob/cwae093","url":null,"abstract":"Galectins are β-galactosyl-binding lectins with key roles in early development, immune regulation, and infectious disease. Influenza A virus (IAV) infects the airway epithelia, and in severe cases may lead to bacterial superinfections and hypercytokinemia, and eventually, to acute respiratory distress syndrome (ARDS) through the breakdown of airway barriers. The detailed mechanisms involved, however, remain poorly understood. Our prior in vivo studies in a murine model system revealed that upon experimental IAV and pneumococcal primary and secondary challenges, respectively, galectin-1 and galectin-3 (Gal-3) are released into the airway and bind to the epithelium that has been desialylated by the viral neuraminidase, contributing to secondary bacterial infection and hypercytokinemia leading to the clinical decline and death of the animals. Here we report the results of in vitro studies that reveal the role of the extracellular Gal-3 in additional detrimental effects on the host by disrupting the integrity of the airway epithelial barrier. IAV infection of the human airway epithelia cell line A549 increased release of Gal-3 and its binding to the A549 desialylated cell surface, notably to the transmembrane signaling receptors CD147 and integrin-β1. Addition of recombinant Gal-3 to A549 monolayers resulted in enhanced expression and release of matrix metalloproteinases, leading to disruption of cell-cell tight junctions, and a significant increase in paracellular permeability. This study reveals a critical mechanism involving Gal-3 that may significantly contribute to the severity of IAV infections by promoting disruption of tight junctions and enhanced permeability of the airway epithelia, potentially leading to lung edema and ARDS.","PeriodicalId":12766,"journal":{"name":"Glycobiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A self-immolative Kdn-glycoside substrate enables high-throughput screening for inhibitors of Kdnases. 一种自褪色的 Kdn-糖苷底物可实现 Kdn 酶抑制剂的高通量筛选。

IF 3.4 3区生物学

Glycobiology Pub Date : 2024-11-21 DOI: 10.1093/glycob/cwae094

Ali Nejatie, Cameron Proceviat, Christina Gros, Elizabeth Steves, Margo M Moore, David J Vocadlo, Andrew J Bennet

{"title":"A self-immolative Kdn-glycoside substrate enables high-throughput screening for inhibitors of Kdnases.","authors":"Ali Nejatie, Cameron Proceviat, Christina Gros, Elizabeth Steves, Margo M Moore, David J Vocadlo, Andrew J Bennet","doi":"10.1093/glycob/cwae094","DOIUrl":"https://doi.org/10.1093/glycob/cwae094","url":null,"abstract":"Aspergillus fumigatus, a filamentous fungus, is an opportunistic pathogen and the major causative agent of the often-fatal disease, invasive aspergillosis (IA). Current treatments for IA are limited due to their high toxicity and/or the emergence of drug resistance; therefore, a need exists for the development of new therapeutics to treat IA. The Kdnase produced by A. fumigatus plays a vital role in maintaining cell wall integrity. As there are no known Kdnases in humans, developing inhibitors of Kdnase from this fungal pathogen is a promising therapeutic approach. The rapid testing of enzymatic activity in a high-throughput screen of large chemical libraries can be an efficient way to find new small molecule lead compounds. Herein we show that a Kdn glycoside with a self-immolative cleavable aglycon is a practical and efficient substrate for a high throughput assay to identify Kdnase inhibitors. We optimized the activity assay and screened over 27,000 compounds from two bioactive chemical libraries as potential inhibitors, and we compared the hit compounds' potency towards Aspergillus terreus and Trichophyton rubrum Kdnases, two other fungal Kdnases. We validated a number of hits and these small molecules are potential leads for the development of novel therapeutics to treat invasive aspergillosis.","PeriodicalId":12766,"journal":{"name":"Glycobiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The 1st International Symposium on GPI and its Deficiency: Bridging Basic Research to Medical Frontiers in PNH and IGD. 第一届 GPI 及其缺陷国际研讨会：连接 PNH 和 IGD 的基础研究与医学前沿。

IF 3.4 3区生物学

Glycobiology Pub Date : 2024-11-12 DOI: 10.1093/glycob/cwae091

Qi Zhang

引用次数: 0

Why Nature Evolved GPI-anchored proteins: Unique Structure Characteristics Enable Versatile Cell Surface Functions. 为什么大自然会进化出 GPI-anchored 蛋白质？独特的结构特征使细胞表面功能多样化

IF 3.4 3区生物学

Glycobiology Pub Date : 2024-11-12 DOI: 10.1093/glycob/cwae089

Qi Zhang, Morihisa Fujita

{"title":"Why Nature Evolved GPI-anchored proteins: Unique Structure Characteristics Enable Versatile Cell Surface Functions.","authors":"Qi Zhang, Morihisa Fujita","doi":"10.1093/glycob/cwae089","DOIUrl":"https://doi.org/10.1093/glycob/cwae089","url":null,"abstract":"It remains a mystery why nature evolved the unique structural characteristics of GPI-anchored proteins (GPI-APs) and continues to sustain the complex, energy-intensive process of synthesizing these proteins. GPI-APs, despite their small size, rely on the coordinated activity of nearly 30 genes for their synthesis and remodeling, raising important evolutionary questions. The biological advantages of GPI-APs lie in their ability to rapidly redistribute across the cell membrane, localize within lipid rafts, utilize unique intracellular trafficking pathways, and function as both membrane-bound and soluble proteins. These properties allow GPI-APs to participate in diverse cellular processes such as synaptic plasticity, immune regulation, and signal transduction, highlighting their indispensable roles. Additionally, the shedding capability of GPI-APs extends their functional reach, adding further versatility to their biological roles. This review not only summarizes these key insights but also explores the broader implications of GPI-APs in cell signaling and disease. By understanding the evolutionary necessity of GPI-APs, we can better appreciate their complexity and potential as therapeutic targets.","PeriodicalId":12766,"journal":{"name":"Glycobiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The diversity of glycan chains in jellyfish mucin of three Cubozoan species: the contrast in molecular evolution rates of the peptide chain and Glycans. 三种腔肠动物的水母粘蛋白中糖链的多样性：肽链和糖的分子进化速度对比。

IF 3.4 3区生物学

Glycobiology Pub Date : 2024-11-05 DOI: 10.1093/glycob/cwae090

Takuma Kaneko, Shinra Tanaka, Minami Sugiyama, Shiori Kaise, Hiroshi Inui, Kiminori Ushida

{"title":"The diversity of glycan chains in jellyfish mucin of three Cubozoan species: the contrast in molecular evolution rates of the peptide chain and Glycans.","authors":"Takuma Kaneko, Shinra Tanaka, Minami Sugiyama, Shiori Kaise, Hiroshi Inui, Kiminori Ushida","doi":"10.1093/glycob/cwae090","DOIUrl":"https://doi.org/10.1093/glycob/cwae090","url":null,"abstract":"The O-glycan composition of jellyfish (JF) mucin (qniumucin: Q-mucin) extracted from three Cubozoan species was studied after the optimization of the purification protocol. Application of a stepwise gradient of ionic strength to anion exchange chromatography (AEXC) was effective for isolating Q-mucin from coexisting impurities. In the three species, the amino acid sequence of the tandem repeat (TR) region in Q-mucin in all three Cubozoans seemed to remain the same as that in all Scyphozoans, although their glycan chains seemed to exhibit clear diversity. In particular, the amounts of acidic moieties on the glycan chains of Q-mucin from the Cubozoans markedly varied even in these genetically close species. In two of the three Cubozoan species, the fraction of disaccharides was large, showing a sharp contrast to that of the glycans of Q-mucin in Scyphozoans. This study also indicates that the simple sequence of TR commonly inherited in all Cubozoan and Scyphozoan JF species after the long term of evolution over 500 M years. According to this research, the glycans and the TR of mucin-type glycoproteins (MTGPs), forming a hierarchical structure, appear to complement each other in the evolutionary changes because the time required for their hereditary conversion is considerably different. The cooperation of these mechanisms is a strategy to achieve the contradictory functions of biosystems, namely species conservation and diversity acquisition.","PeriodicalId":12766,"journal":{"name":"Glycobiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The crystal structure of Nictaba reveals its carbohydrate-binding properties and a new lectin dimerization mode. Nictaba 的晶体结构揭示了其碳水化合物结合特性和一种新的凝集素二聚化模式。

IF 3.4 3区生物学

Glycobiology Pub Date : 2024-10-22 DOI: 10.1093/glycob/cwae087

Yehudi Bloch, Vinicius J S Osterne, Savvas N Savvides, Els J M Van Damme

{"title":"The crystal structure of Nictaba reveals its carbohydrate-binding properties and a new lectin dimerization mode.","authors":"Yehudi Bloch, Vinicius J S Osterne, Savvas N Savvides, Els J M Van Damme","doi":"10.1093/glycob/cwae087","DOIUrl":"https://doi.org/10.1093/glycob/cwae087","url":null,"abstract":"Nictaba is a (GlcNAc)n-binding, stress-inducible lectin from Nicotiana tabacum that serves as a representative for the Nictaba-related lectins, a group of proteins that play pivotal roles in plant defense mechanisms and stress response pathways. Despite extensive research into biological activities and physiological role(s) of the lectin, the three-dimensional structure of Nictaba remained largely unknown. Here, we report crystal structures for Nictaba in the apo form and bound to chitotriose. The structures reveal that the Nictaba protomer has a jelly-roll fold, similar to the cucumber lectin Cus17, but exhibit a unique and previously unseen mode of dimerization. The chitotriose binding mode, similar to Cus17, centers around the central GlcNAc residue, providing insights into the determinants of specificity of Nictaba towards carbohydrate structures. By integrating these structural insights with inputs from glycan arrays, molecular docking, and molecular dynamics simulations, we propose that Nictaba employs a single carbohydrate-recognition domain within each of the two subunits in the dimer to display pronounced specificity towards GlcNAc-containing carbohydrates. Furthermore, we identified amino acid residues involved in the extended binding site capable of accommodating structurally diverse high-mannose and complex N-glycans. Glycan array and in silico analyses revealed interactions centered around the conserved Man3GlcNAc2 core, explaining the broad recognition of N-glycan structures. Collectively, the structural and biochemical insights presented here fill a void into the atlas of lectin structure-function relationships and pave the way for future developments in plant stress biology and lectin-based applications.","PeriodicalId":12766,"journal":{"name":"Glycobiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mucin-driven ecological interactions in an in vitro synthetic community of human gut microbes. 体外合成人体肠道微生物群落中由粘蛋白驱动的生态相互作用。

IF 3.4 3区生物学

Glycobiology Pub Date : 2024-10-10 DOI: 10.1093/glycob/cwae085

Maryse D Berkhout, Athanasia Ioannou, Carol Ram, Sjef Boeren, Caroline M Plugge, Clara Belzer

{"title":"Mucin-driven ecological interactions in an in vitro synthetic community of human gut microbes.","authors":"Maryse D Berkhout, Athanasia Ioannou, Carol Ram, Sjef Boeren, Caroline M Plugge, Clara Belzer","doi":"10.1093/glycob/cwae085","DOIUrl":"https://doi.org/10.1093/glycob/cwae085","url":null,"abstract":"Specific human gut microbes inhabit the outer mucus layer of the gastrointestinal tract. Certain residents of this niche can degrade the large and complex mucin glycoproteins that constitute this layer and utilise the degradation products for their metabolism. In turn, this microbial mucin degradation drives specific microbiological ecological interactions in the human gut mucus layer. However, the exact nature of these interactions remains unknown. In this study, we designed and studied an in vitro mucin-degrading synthetic community that included mucin O-glycan degraders and cross-feeding microorganisms by monitoring community composition and dynamics through a combination of 16S rRNA gene amplicon sequencing and qPCR, mucin glycan degradation with PGC-LC-MS/MS, production of mucin-degrading enzymes and other proteins through metaproteomics, and metabolite production with HPLC. We demonstrated that specialist and generalist mucin O-glycan degraders stably co-exist and found evidence for cross-feeding relationships. Cross-feeding on the products of mucin degradation by other gut microbes resulted in butyrate production, hydrogenotrophic acetogenesis, sulfate reduction and methanogenesis. Metaproteomics analysis revealed that mucin glycan degraders Akkermansia muciniphila, Bacteroides spp. and Ruminococcus torques together contributed 92% of the total mucin O-glycan degrading enzyme pool of this community. Furthermore, comparative proteomics showed that in response to cultivation in a community compared to monoculture, mucin glycan degraders increased carbohydrate-active enzymes whereas we also found indications for niche differentiation. These results confirm the complexity of mucin-driven microbiological ecological interactions and the intricate role of carbohydrate-active enzymes in the human gut mucus layer.","PeriodicalId":12766,"journal":{"name":"Glycobiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bioinformatics-aided function exploration of GH29 fucosidases from human gut Parabacteroides. 生物信息学辅助探索人类肠道副杆菌 GH29 粘多糖酶的功能。

IF 3.4 3区生物学

Glycobiology Pub Date : 2024-10-10 DOI: 10.1093/glycob/cwae086

Haiyang Wu, Qingxin Li, Jin Chuan Wu

{"title":"Bioinformatics-aided function exploration of GH29 fucosidases from human gut Parabacteroides.","authors":"Haiyang Wu, Qingxin Li, Jin Chuan Wu","doi":"10.1093/glycob/cwae086","DOIUrl":"https://doi.org/10.1093/glycob/cwae086","url":null,"abstract":"Gut microbes produce α-l-fucosidases critical for utilizing human milk oligosaccharides, mucosal and dietary glycans. Although gut Parabacteroides have garnered attention for their impact on host health and disease, their CAZymes remain poorly studied. CAZome analysis of eleven gut Parabacteroides type strains revealed their capacity to degrade mucin O-glycans. Their abundance of GH29 fucosidases caught our attention, and we predicted the functional profiles of 46 GH29 fucosidases using in silico approaches. Our findings showed diverse linkages specificities and species-specific distributions, with over half of GH29 enzymes functioning as α1,3/4 fucosidases, essential for acting on Lewis antigen epitopes of mucin O-glycans. We further enzymatically validated 4 novel GH29 sequences from poorly characterized groups. PgoldGH29A (cluster37 GH29BERT, GH29:75.1 CUPP) does not act on tested natural substrates. PgoldGH29B (cluster1 GH29BERT, GH29:84.1 CUPP) functions as a strict α1,3/4 fucosidase. PgoldGH29C (cluster14 GH29BERT, GH29:29.1 CUPP) displays unprecedented substrate specificity for α1,2/3/4 disaccharides. PgoldGH29D (cluster4 GH29BERT, GH29:6.2 CUPP) acts on α1,2/3/4/6 linkages similar to enzymes from GH29:6.1 CUPP but prefers disaccharides over trisaccharides. These results suggest that PgoldGH29B and PgoldGH29D can contribute to mucin O-glycan degradation via their α1,3/4 and α1,2 fucosidase activity, respectively, while the natural substrates of PgoldGH29A and PgoldGH29C may be irrelevant to host-glycans. These insights enhance our understanding of the ecological niches inhabited by gut Parabacteroides and may guide similar exploration in other intriguing gut microbial species.","PeriodicalId":12766,"journal":{"name":"Glycobiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Diversity of human salivary heparan sulfate. 人类唾液硫酸肝素的多样性。

IF 3.4 3区生物学

Glycobiology Pub Date : 2024-10-03 DOI: 10.1093/glycob/cwae084

Charlotte B Spliid, Sanjay Mehta, Mark M Fuster, Cameron Martino, Claire L Morris, Nharae Lee, Ivan Florentino, Khang Tong, Lin Liu, Gail Ackermann, Rob Knight, Jeffrey D Esko, Tatiana Hurtado De Mendoza

{"title":"Diversity of human salivary heparan sulfate.","authors":"Charlotte B Spliid, Sanjay Mehta, Mark M Fuster, Cameron Martino, Claire L Morris, Nharae Lee, Ivan Florentino, Khang Tong, Lin Liu, Gail Ackermann, Rob Knight, Jeffrey D Esko, Tatiana Hurtado De Mendoza","doi":"10.1093/glycob/cwae084","DOIUrl":"https://doi.org/10.1093/glycob/cwae084","url":null,"abstract":"The human oral cavity and upper airway serves as an early barrier and reservoir in the transmission of SARS-CoV-2. Saliva in this microenvironment may serve as a key host factor that can modulate susceptibility to infection and eventual infection of the lower respiratory tract. We sought to analyze the content and composition of heparan sulfate, a glycosaminoglycan identified as an important co-receptor for viral entry, and whether there is any correlation with SARS-CoV-2 infection. We enlisted 98 participants stratified by age, gender, race, and COVID-19 history. Notably, the concentration of heparan sulfate in saliva increased with age, and its composition showed a wide range of variability within each age group independently of age. Heparan sulfate concentration and composition did not differ significantly with gender, ethnicity or race. Compared to patients with no COVID-19 history, patients with previous infection had a similar salivary heparan sulfate concentration, but significant increases in overall sulfation were noted. Moreover, in a subset of participants, for which data was available pre- and post- infection, significant elevation in N-sulfoglucosamine in heparan sulfate was observed post- COVID-19. Examination of salivary bacterial 16S rRNA, showed a significant reduction in species predicted to possess heparan sulfate-modifying capacity among participants >60 years old, which correlates with the increase in heparan sulfate content in older individuals. These findings demonstrate a surprisingly wide variation in heparan sulfate content and composition in saliva across the sampled population and confirm other findings showing variation in content and composition of glycosaminoglycans in blood and urine.","PeriodicalId":12766,"journal":{"name":"Glycobiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Compromised CDK12 activity causes dependency on the high activity of O-GlcNAc transferase. CDK12 活性下降会导致对高活性 O-GlcNAc 转移酶的依赖。

IF 3.4 3区生物学

Glycobiology Pub Date : 2024-10-03 DOI: 10.1093/glycob/cwae081

Satu Pallasaho, Aishwarya Gondane, Julia Kutz, Jing Liang, Shivani Yalala, Damien Y Duveau, Helmut Pospiech, Craig J Thomas, Massimo Loda, Harri M Itkonen

{"title":"Compromised CDK12 activity causes dependency on the high activity of O-GlcNAc transferase.","authors":"Satu Pallasaho, Aishwarya Gondane, Julia Kutz, Jing Liang, Shivani Yalala, Damien Y Duveau, Helmut Pospiech, Craig J Thomas, Massimo Loda, Harri M Itkonen","doi":"10.1093/glycob/cwae081","DOIUrl":"https://doi.org/10.1093/glycob/cwae081","url":null,"abstract":"O-GlcNAc transferase (OGT) coordinates with regulators of transcription, including cyclin-dependent kinase 12 (CDK12), the major transcription elongation kinase. Here, we use inhibitor- and knockdown-based strategies to show that co-targeting of OGT and CDK12 is toxic to prostate cancer cells. OGT catalyzes all nucleocytoplasmic O-GlcNAcylation and due to its essentiality in higher eukaryotes, it is not an ideal drug target. Our glycoproteomics-data revealed that short-term CDK12 inhibition induces hyper-O-GlcNAcylation of the spliceosome-machinery in different models of prostate cancer. By integrating our glycoproteomics-, gene essentiality- and clinical-data from CDK12 mutant prostate cancer patients, we identify the non-essential serine-arginine protein kinase 1 (SRPK1) as a synthetic lethal partner with CDK12-inactivation. Both normal and cancer cells become highly sensitive against inhibitors of OGT and SRPK1 if they have lowered activity of CDK12. Inactivating mutations in CDK12 are enriched in aggressive prostate cancer, and we propose that these patients would benefit from therapy targeting the spliceosome.","PeriodicalId":12766,"journal":{"name":"Glycobiology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0