The FEBS journal最新文献_第3页

Structural and biophysical characterisation of ubiquitin variants that inhibit the ubiquitin conjugating enzyme Ube2d2. 抑制泛素连接酶 Ube2d2 的泛素变体的结构和生物物理特征。

The FEBS journal Pub Date : 2024-10-29 DOI: 10.1111/febs.17311

Jeffery M R B McAlpine, Gene Zhu, Nicholas Pudjihartono, Joan Teyra, Michael J Currie, Zachary D Tillett, Renwick C J Dobson, Sachdev S Sidhu, Catherine L Day, Adam J Middleton

{"title":"Structural and biophysical characterisation of ubiquitin variants that inhibit the ubiquitin conjugating enzyme Ube2d2.","authors":"Jeffery M R B McAlpine, Gene Zhu, Nicholas Pudjihartono, Joan Teyra, Michael J Currie, Zachary D Tillett, Renwick C J Dobson, Sachdev S Sidhu, Catherine L Day, Adam J Middleton","doi":"10.1111/febs.17311","DOIUrl":"https://doi.org/10.1111/febs.17311","url":null,"abstract":"The ubiquitin-conjugating E2 enzymes play a central role in ubiquitin transfer. Disruptions to the ubiquitin system are implicated in multiple diseases, and as a result, molecules that modulate the activity of the ubiquitin system are of interest. E2 enzyme function relies on interactions with partner proteins, and the disruption of these is an effective way to modulate activity. Here, we report the discovery of ubiquitin variants (UbVs) that inhibit the E2 enzyme, Ube2d2 (UbcH5b). The six UbVs identified inhibit ubiquitin chain building, and the structural and biophysical characterisation of two of these demonstrate they bind to Ube2d2 with low micromolar affinity and high specificity. Both characterised UbVs bind at a site that overlaps with E1 binding, while the more inhibitory UbV has an additional binding site that blocks a critical non-covalent ubiquitin-binding site on the E2 enzyme. The discovery of novel protein-based ubiquitin derivatives that inhibit protein-protein interactions is an important step towards discovering small molecules that inhibit the activity of E2 enzymes. Furthermore, the specificity of the UbVs within the Ube2d family suggests that it may be possible to develop tools to selectively inhibit highly related E2 enzymes.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The small molecule ZPD-2 inhibits the aggregation and seeded polymerisation of C-terminally truncated α-Synuclein. 小分子 ZPD-2 可抑制 C 端截短的α-突触核蛋白的聚集和种子聚合。

The FEBS journal Pub Date : 2024-10-27 DOI: 10.1111/febs.17310

Samuel Peña-Díaz, Salvador Ventura

引用次数: 0

The structure of the IL-11 signalling complex provides insight into receptor variants associated with craniosynostosis. IL-11信号复合体的结构使人们能够深入了解与颅骨发育不良有关的受体变异。

The FEBS journal Pub Date : 2024-10-27 DOI: 10.1111/febs.17307

Darlene D Sentosa, Riley D Metcalfe, Natalie A Sims, Tracy L Putoczki, Michael D W Griffin

{"title":"The structure of the IL-11 signalling complex provides insight into receptor variants associated with craniosynostosis.","authors":"Darlene D Sentosa, Riley D Metcalfe, Natalie A Sims, Tracy L Putoczki, Michael D W Griffin","doi":"10.1111/febs.17307","DOIUrl":"https://doi.org/10.1111/febs.17307","url":null,"abstract":"Interleukin 11 (IL-11), a member of the IL-6 family of cytokines, has roles in haematopoiesis, inflammation, bone metabolism, and craniofacial development. IL-11 also has pathological roles in chronic inflammatory diseases, fibrosis, and cancer. In this structural snapshot, we explore our recently published cryo-EM structure of the human IL-11 signalling complex to understand the molecular mechanisms of complex formation and disease-associated mutations. IL-11 signals by binding to its cell surface receptors, the IL-11 receptor α subunit (IL-11Rα) and glycoprotein 130 (gp130), to form a hexameric signalling complex. We examine the locations within the complex of receptor sequence variants that are associated with craniosynostosis and craniosynostosis-like phenotypes and speculate on potential molecular mechanisms leading to defects in signalling function. While these causative amino acid sequence changes in IL-11Rα are generally distal to interfaces between components of the complex, important structural residues are highly represented, including proline residues, cysteine residues involved in disulfide bonds, and residues within or surrounding the tryptophan-arginine ladder. We also note the locations and potential effects of amino acid substitutions within the extracellular domains of gp130 that are associated with craniosynostosis. As focus on the physiological and pathological functions of IL-11 grows, the importance of high-resolution structural knowledge of IL-11 signalling to understand disease-associated mutations and to inform therapeutic strategies will only increase.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142515668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A ZO-2 scaffolding mechanism regulates the Hippo signalling pathway. ZO-2支架机制调节Hippo信号通路。

The FEBS journal Pub Date : 2024-10-27 DOI: 10.1111/febs.17304

Olivia Xuan Liu, Lester Bocheng Lin, Soumya Bunk, Tiweng Chew, Selwin K Wu, Fumio Motegi, Boon Chuan Low

引用次数: 0

Stoichiometry of ligand binding and role of C-terminal lysines in Mycobacterium tuberculosis and human GAPDH multifunctionality. 配体结合的化学计量以及 C 端赖氨酸在结核分枝杆菌和人类 GAPDH 多功能性中的作用。

The FEBS journal Pub Date : 2024-10-22 DOI: 10.1111/febs.17298

Ajay Kumar, Rajender Kumar, Vishant Mahendra Boradia, Himanshu Malhotra, Adarsh Kumar, Sriraj Seth, Prabha Garg, Subramanian Karthikeyan, Manoj Raje, Chaaya Iyengar Raje

{"title":"Stoichiometry of ligand binding and role of C-terminal lysines in Mycobacterium tuberculosis and human GAPDH multifunctionality.","authors":"Ajay Kumar, Rajender Kumar, Vishant Mahendra Boradia, Himanshu Malhotra, Adarsh Kumar, Sriraj Seth, Prabha Garg, Subramanian Karthikeyan, Manoj Raje, Chaaya Iyengar Raje","doi":"10.1111/febs.17298","DOIUrl":"https://doi.org/10.1111/febs.17298","url":null,"abstract":"Glyceraldehyde-3-phosphate-dehydrogenase (GAPDH; EC1.2.1.12) has several functions in Mycobacterium tuberculosis (Mtb) and the human host. Apart from its role in glycolysis, it serves both as a cell surface and a secreted receptor for plasmin(ogen) (Plg/Plm), transferrin (Tf), and lactoferrin (Lf). Plg sequestration by Mtb GAPDH facilitates bacterial adhesion and tissue invasion, while an equivalent interaction with host GAPDH regulates immune cell migration. In both, host and microbe, internalization of Tf/Lf-GAPDH complexes serves as a route for iron acquisition. To date, the structure of Mtb GAPDH or the residues involved in these moonlighting interactions have not been identified. This study provides the first known X-ray crystal structure of Mtb GAPDH. Through further mutagenesis and functional assays, we found that the C-terminal lysines of Mtb and human GAPDH affect enzyme activity and ligand binding. We also establish the stoichiometry of Plg, Tf and Lf interactions with the GAPDH tetramer. Lastly, molecular simulation studies reveal the interactions of the C-terminal lysine residues.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142515666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Macrophages and autophagy: partners in crime. 巨噬细胞与自噬：犯罪伙伴

The FEBS journal Pub Date : 2024-10-22 DOI: 10.1111/febs.17305

Alessandra Vitaliti, Alessio Reggio, Alessandro Palma

引用次数: 0

Thioredoxin reductase inhibition and glutathione depletion mediated by glaucocalyxin A promote intracellular disulfide stress in gastric cancer cells. 硫氧还蛋白还原酶抑制和谷胱甘肽耗竭由青光素 A 介导，可促进胃癌细胞内的二硫化物应激。

The FEBS journal Pub Date : 2024-10-21 DOI: 10.1111/febs.17301

Ling Wang, Shibo Sun, Haowen Liu, Qiuyu Zhang, Yao Meng, Fan Sun, Jianjun Zhang, Haiyan Liu, Weiping Xu, Zhiwei Ye, Jie Zhang, Bingbing Sun, Jianqiang Xu

{"title":"Thioredoxin reductase inhibition and glutathione depletion mediated by glaucocalyxin A promote intracellular disulfide stress in gastric cancer cells.","authors":"Ling Wang, Shibo Sun, Haowen Liu, Qiuyu Zhang, Yao Meng, Fan Sun, Jianjun Zhang, Haiyan Liu, Weiping Xu, Zhiwei Ye, Jie Zhang, Bingbing Sun, Jianqiang Xu","doi":"10.1111/febs.17301","DOIUrl":"https://doi.org/10.1111/febs.17301","url":null,"abstract":"Thioredoxin reductase 1 (TXNRD1) has been identified as one of the promising chemotherapeutic targets in cancer cells. Therefore, a novel TXNRD1 inhibitor could accelerate chemotherapy in clinical anticancer research. In this study, glaucocalyxin A (GlauA), a natural diterpene extracted from Rabdosia japonica var. glaucocalyx, was identified as a novel inhibitor of TXNRD1. We found that GlauA effectively inhibited recombinant TXNRD1 and reduced its activity in gastric cancer cells without affecting the enzyme's expression level. Mechanistically, the selenocysteine residue (U498) of TXNRD1 was irreversibly modified by GlauA through a Michael addition. Additionally, GlauA formed a covalent adduct with glutathione (GSH) and disrupted cellular redox balance by depleting cellular GSH. The inhibition of TXNRD1 and depletion of GSH by GlauA conferred its cytotoxic effects in spheroid culture and Transwell assays in AGS cells. The disulfide stress induced cytotoxicity of GlauA could be mitigated by adding reducing agents, such as DTT and β-ME. Furthermore, the FDA-approval drug auranofin, a TXNRD1 inhibitor, triggered oligomerization of the cytoskeletal protein Talin-1 in AGS cells, indicating that inhibiting TXNRD1 triggered disulfide stress. In conclusion, this study uncovered GlauA as an efficient inhibitor of TXNRD1 and demonstrated the potential of TXNRD1 inhibition as an effective anticancer strategy by disrupting redox homeostasis and inducing disulfide stress.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the ubiquitin-proteasome system. FBXW7通过连接伴侣介导的自噬和泛素-蛋白酶体系统的新机制调控PGC-1α。

The FEBS journal Pub Date : 2024-10-21 DOI: 10.1111/febs.17276

Simona Eleuteri, Bao Wang, Gianni Cutillo, Tracy Shi Zhang Fang, Kai Tao, Yan Qu, Qian Yang, Wenyi Wei, David K Simon

{"title":"PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the ubiquitin-proteasome system.","authors":"Simona Eleuteri, Bao Wang, Gianni Cutillo, Tracy Shi Zhang Fang, Kai Tao, Yan Qu, Qian Yang, Wenyi Wei, David K Simon","doi":"10.1111/febs.17276","DOIUrl":"https://doi.org/10.1111/febs.17276","url":null,"abstract":"Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and antioxidative defenses, and it may play a critical role in Parkinson's disease (PD). F-box/WD repeat domain-containing protein (FBXW7), an E3 protein ligase, promotes the degradation of substrate proteins through the ubiquitin-proteasome system (UPS) and leads to the clearance of PGC-1α. Here, we elucidate a novel post-translational mechanism for regulating PGC-1α levels in neurons. We show that enhancing chaperone-mediated autophagy (CMA) activity promotes the CMA-mediated degradation of FBXW7 and consequently increases PGC-1α. We confirm the relevance of this pathway in vivo by showing decreased FBXW7 and increased PGC-1α as a result of boosting CMA selectively in dopaminergic (DA) neurons by overexpressing lysosomal-associated membrane protein 2A (LAMP2A) in TH-Cre-LAMP2-loxp conditional mice. We further demonstrate that these mice are protected against MPTP-induced oxidative stress and neurodegeneration. These results highlight a novel regulatory pathway for PGC-1α in DA neurons and suggest targeted increasing of CMA or decreasing FBXW7 in DA neurons as potential neuroprotective strategies in PD.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TBK1 is involved in M-CSF-induced macrophage polarization through mediating the IRF5/IRF4 axis. TBK1 通过介导 IRF5/IRF4 轴参与 M-CSF 诱导的巨噬细胞极化。

The FEBS journal Pub Date : 2024-10-21 DOI: 10.1111/febs.17297

Yuanyuan Li, Le Ji, Chang Liu, Juanjuan Li, Di Wen, Zhongyao Li, Lishuang Yu, Moran Guo, Shaoran Zhang, Weisong Duan, Le Yi, Yue Bi, Hui Bu, Chunyan Li, Yakun Liu

{"title":"TBK1 is involved in M-CSF-induced macrophage polarization through mediating the IRF5/IRF4 axis.","authors":"Yuanyuan Li, Le Ji, Chang Liu, Juanjuan Li, Di Wen, Zhongyao Li, Lishuang Yu, Moran Guo, Shaoran Zhang, Weisong Duan, Le Yi, Yue Bi, Hui Bu, Chunyan Li, Yakun Liu","doi":"10.1111/febs.17297","DOIUrl":"https://doi.org/10.1111/febs.17297","url":null,"abstract":"TANK binding kinase 1 (TBK1) is an important kinase that is involved in innate immunity and tumor development. Macrophage colony-stimulating factor (M-CSF) regulates the differentiation and function of macrophages towards the immunosuppressive M2 phenotype in the glioblastoma multiforme microenvironment. The role of TBK1 in macrophages, especially in regulating macrophage polarization in response to M-CSF stimulation, remains unclear. Here, we found high TBK1 expression in human glioma-infiltrating myeloid cells and that phosphorylated TBK1 was highly expressed in M-CSF-stimulated macrophages but not in granulocyte-macrophage CSF-induced macrophages (granulocyte-macrophage-CSF is involved in the polarization of M1 macrophages). Conditional deletion of TBK1 in myeloid cells induced M-CSF-stimulated bone marrow-derived macrophages to exhibit a proinflammatory M1-like phenotype with increased protein expression of CD86, interleukin-1β and tumor necrosis factor-α, as well as decreased expression of arginase 1. Mechanistically, TBK1 deletion or inhibition by amlexanox or GSK8612 reduced the expression of the transcription factor interferon-regulatory factor (IRF)4 and increased the level of IRF5 activation in macrophages stimulated with M-CSF, leading to an M1-like profile with highly proinflammatory factors. IRF5 deletion reversed the effect of TBK1 inhibition on M-CSF-mediated macrophage polarization. Our findings suggest that TBK1 contributes to the regulation of macrophage polarization in response to M-CSF stimulation partly through the IRF5/IRF4 axis.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The deficiency of ALKBH5 contributes to hepatic lipid deposition by impairing VPS11-dependent autophagic flux. ALKBH5 的缺乏会损害 VPS11 依赖性自噬通量，从而导致肝脏脂质沉积。

The FEBS journal Pub Date : 2024-10-21 DOI: 10.1111/febs.17299

Linghuan Li, Yuanhai Sun, Lingqin Li, Wanfang Zheng, Weiwei Zha, Tengjiao Zhao, Guangyao Zhu, Hanbing Li

{"title":"The deficiency of ALKBH5 contributes to hepatic lipid deposition by impairing VPS11-dependent autophagic flux.","authors":"Linghuan Li, Yuanhai Sun, Lingqin Li, Wanfang Zheng, Weiwei Zha, Tengjiao Zhao, Guangyao Zhu, Hanbing Li","doi":"10.1111/febs.17299","DOIUrl":"https://doi.org/10.1111/febs.17299","url":null,"abstract":"Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Hepatic lipid deposition is a key factor in the development of NAFLD. N6-methyladenosine (m6A) modification, the most prevalent mRNA modification in eukaryotic cells, plays an important role in regulating hepatic lipid metabolism. However, its potential role in hepatic lipid deposition remains poorly understood. Histological and immunohistochemistry studies were used to investigate lipid deposition in free fatty acids (FFAs)-incubated LO2 cells, high-fat diet-fed mice models and clinical samples. Stable overexpression and knockdown of AlkB homolog 5 (ALKBH5) was manipulated to investigate the effects of ALKBH5 on m6A methylation and lipid metabolism in hepatocytes. RNA-sequencing transcriptome analysis and methylated RNA immunoprecipitation-quantitative-PCR analysis were used to reveal the potential downstream molecular targets of ALKBH5. ALKBH5 was down-regulated in fatty liver compared to normal liver in both humans and mice. Overexpression of ALKBH5 significantly improved FFA-induced lipid accumulation and promoted autophagosome-lysosome fusion in hepatocytes. Meanwhile, knockdown of ALKBH5 significantly increased the expression of microtubule-associated protein 1A/1B-light chain 3B and Sequestosome 1, leading to impaired autophagic flux and further lipid deposition in hepatocytes under FFA incubation. Overexpression of vacuolar protein sorting 11 (VPS11) reversed FFA-induced lipid accumulation in ALKBH5-silenced hepatocytes. Mechanistically, ALKBH5 alleviated hepatic lipid deposition and impaired autophagic flux by removing the m6A modification on VPS11 mRNA to promote its translation. Collectively, our findings revealed an epigenetic mechanism by which ALKBH5 alleviates hepatic lipid deposition by restoring VPS11-dependent autophagic flux, providing a potential target to counteract NAFLD.","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0