Biochemical Journal最新文献_第10页

Loss of the methylarginine reader function of SND1 confers resistance to hepatocellular carcinoma. SND1甲基精氨酸读写器功能的丧失赋予了对肝细胞癌的耐药性。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2023-11-29 DOI: 10.1042/BCJ20230384

Tanner Wright, Yalong Wang, Sabrina A Stratton, Manu Sebastian, Bin Liu, David G Johnson, Mark T Bedford

{"title":"Loss of the methylarginine reader function of SND1 confers resistance to hepatocellular carcinoma.","authors":"Tanner Wright, Yalong Wang, Sabrina A Stratton, Manu Sebastian, Bin Liu, David G Johnson, Mark T Bedford","doi":"10.1042/BCJ20230384","DOIUrl":"10.1042/BCJ20230384","url":null,"abstract":"Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that 'reads' methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings by developing two genetically engineered SND1 mouse models, an Snd1 knockout (Snd1 KO) and an Snd1 Tudor domain-mutated (Snd1 KI) mouse, whose mutant SND1 can no longer recognize PRMT5-catalyzed methylarginine marks. Quantitative PCR analysis of normal, KO, and KI liver samples revealed a role for the SND1 Tudor domain in regulating the expression of genes encoding major acute phase proteins, which could provide mechanistic insight into SND1 function in a tumor setting. Prior studies indicated that ectopic overexpression of SND1 in the mouse liver dramatically accelerates the development of diethylnitrosamine (DEN)-induced HCC. Thus, we tested the combined effects of DEN and SND1 loss or mutation on the development of HCC. We found that both Snd1 KO and Snd1 KI mice were partially protected against malignant tumor development following exposure to DEN. These results support the development of small molecule inhibitors that target the SND1 Tudor domain or the use of upstream PRMT5 inhibitors, as novel treatments for HCC.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10860161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71410432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Plant adaptation to climate change. 植物对气候变化的适应。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-29 DOI: 10.1042/BCJ20220580

Christine H Foyer, Ilse Kranner

引用次数: 0

Leukotriene B4 receptor 1 (BLT1) does not mediate disease progression in a mouse model of liver fibrosis. 白三烯B4受体1 (BLT1)在小鼠肝纤维化模型中不介导疾病进展。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2023-11-28 DOI: 10.1042/BCJ20230422

Erin Coyne, Yilin Nie, Desiree Abdurrachim, Charlene Lin Zhi Ong, Yongqi Zhou, Asad Abu Bakar Ali, Stacey Meyers, Jeff Grein, Wendy Blumenschein, Brendan Gongol, Yang Liu, Cedric Lorenz Hugelshofer, Ester Carballo-Jane, Saswata Talukdar

{"title":"Leukotriene B4 receptor 1 (BLT1) does not mediate disease progression in a mouse model of liver fibrosis.","authors":"Erin Coyne, Yilin Nie, Desiree Abdurrachim, Charlene Lin Zhi Ong, Yongqi Zhou, Asad Abu Bakar Ali, Stacey Meyers, Jeff Grein, Wendy Blumenschein, Brendan Gongol, Yang Liu, Cedric Lorenz Hugelshofer, Ester Carballo-Jane, Saswata Talukdar","doi":"10.1042/BCJ20230422","DOIUrl":"10.1042/BCJ20230422","url":null,"abstract":"MASH is a prevalent liver disease that can progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and ultimately death, but there are no approved therapies. Leukotriene B4 (LTB4) is a potent pro-inflammatory chemoattractant that drives macrophage and neutrophil chemotaxis, and genetic loss or inhibition of its high affinity receptor, leukotriene B4 receptor 1 (BLT1), results in improved insulin sensitivity and decreased hepatic steatosis. To validate the therapeutic efficacy of BLT1 inhibition in an inflammatory and pro-fibrotic mouse model of MASH and fibrosis, mice were challenged with a choline-deficient, L-amino acid defined high fat diet and treated with a BLT1 antagonist at 30 or 90 mg/kg for 8 weeks. Liver function, histology, and gene expression were evaluated at the end of the study. Treatment with the BLT1 antagonist significantly reduced plasma lipids and liver steatosis but had no impact on liver injury biomarkers or histological endpoints such as inflammation, ballooning, or fibrosis compared to control. Artificial intelligence-powered digital pathology analysis revealed a significant reduction in steatosis co-localized fibrosis in livers treated with the BLT1 antagonist. Liver RNA-seq and pathway analyses revealed significant changes in fatty acid, arachidonic acid, and eicosanoid metabolic pathways with BLT1 antagonist treatment, however, these changes were not sufficient to impact inflammation and fibrosis endpoints. Targeting this LTB4-BLT1 axis with a small molecule inhibitor in animal models of chronic liver disease should be considered with caution, and additional studies are warranted to understand the mechanistic nuances of BLT1 inhibition in the context of MASH and liver fibrosis.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138443690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting bacterial degradation machinery as an antibacterial strategy. 将细菌降解机制作为一种抗菌策略。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-15 DOI: 10.1042/BCJ20230191

Radoslav Petkov, Amy H Camp, Rivka L Isaacson, James H Torpey

引用次数: 0

Biochemical investigations of polyphenol degradation enzymes in the phototrophic bacterium Rubrivivax gelatinosus. 凝胶状嗜光细菌Rubrivivax多酚降解酶的生化研究。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-15 DOI: 10.1042/BCJ20230387

Mengyu Cui, Yifeng Wei, Jason Tan, Tong Li, Xinan Jiao, Yan Zhou

{"title":"Biochemical investigations of polyphenol degradation enzymes in the phototrophic bacterium Rubrivivax gelatinosus.","authors":"Mengyu Cui, Yifeng Wei, Jason Tan, Tong Li, Xinan Jiao, Yan Zhou","doi":"10.1042/BCJ20230387","DOIUrl":"10.1042/BCJ20230387","url":null,"abstract":"Phloroglucinol (1,3,5-trihydroxybenzene) is an important intermediate in the degradation of flavonoids and tannins by anaerobic bacteria. Recent studies have shed light on the enzymatic mechanism of phloroglucinol degradation in butyrate-forming anaerobic bacteria, including environmental and intestinal bacteria such as Clostridium and Flavonifractor sp. Phloroglucinol degradation gene clusters have also been identified in other metabolically diverse bacteria, although the polyphenol metabolism of these microorganisms remain largely unexplored. Here, we describe biochemical studies of polyphenol degradation enzymes found in the purple non-sulfur bacterium Rubrivivax gelatinosus IL144, an anaerobic photoheterotroph reported to utilize diverse organic compounds as carbon sources for growth. In addition to the phloroglucinol reductase and dihydrophloroglucinol cyclohydrolase that catalyze phloroglucinol degradation, we characterize a Mn2+-dependent phloretin hydrolase that catalyzes the cleavage of phloretin into phloroglucinol and phloretic acid. We also report a Mn2+-dependent decarboxylase (DeC) that catalyzes the reversible decarboxylation of 2,4,6-trihydroxybenzoate to form phloroglucinol. A bioinformatics search led to the identification of DeC homologs in diverse soil and gut bacteria, and biochemical studies of a DeC homolog from the human gut bacterium Flavonifractor plautii demonstrated that it is also a 2,4,6-trihydroxybenzoate decarboxylase. Our study expands the range of enzymatic mechanisms for phloroglucinol formation, and provides further biochemical insight into polyphenol metabolism in the anaerobic biosphere.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71410431","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

Interactions of mitochondrial and skeletal muscle biology in mitochondrial myopathy. 线粒体肌病中线粒体和骨骼肌生物学的相互作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-15 DOI: 10.1042/BCJ20220233

Valeria Di Leo, Tiago M Bernardino Gomes, Amy E Vincent

{"title":"Interactions of mitochondrial and skeletal muscle biology in mitochondrial myopathy.","authors":"Valeria Di Leo, Tiago M Bernardino Gomes, Amy E Vincent","doi":"10.1042/BCJ20220233","DOIUrl":"10.1042/BCJ20220233","url":null,"abstract":"Mitochondrial dysfunction in skeletal muscle fibres occurs with both healthy aging and a range of neuromuscular diseases. The impact of mitochondrial dysfunction in skeletal muscle and the way muscle fibres adapt to this dysfunction is important to understand disease mechanisms and to develop therapeutic interventions. Furthermore, interactions between mitochondrial dysfunction and skeletal muscle biology, in mitochondrial myopathy, likely have important implications for normal muscle function and physiology. In this review, we will try to give an overview of what is known to date about these interactions including metabolic remodelling, mitochondrial morphology, mitochondrial turnover, cellular processes and muscle cell structure and function. Each of these topics is at a different stage of understanding, with some being well researched and understood, and others in their infancy. Furthermore, some of what we know comes from disease models. Whilst some findings are confirmed in humans, where this is not yet the case, we must be cautious in interpreting findings in the context of human muscle and disease. Here, our goal is to discuss what is known, highlight what is unknown and give a perspective on the future direction of research in this area.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107590120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activating mutations drive human MEK1 kinase using a gear-shifting mechanism. 激活突变利用变速机制驱动人类MEK1激酶。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-15 DOI: 10.1042/BCJ20230281

Keshav Patil, Yiming Wang, Zhangtao Chen, Krishna Suresh, Ravi Radhakrishnan

{"title":"Activating mutations drive human MEK1 kinase using a gear-shifting mechanism.","authors":"Keshav Patil, Yiming Wang, Zhangtao Chen, Krishna Suresh, Ravi Radhakrishnan","doi":"10.1042/BCJ20230281","DOIUrl":"10.1042/BCJ20230281","url":null,"abstract":"There is an unmet need to classify cancer-promoting kinase mutations in a mechanistically cognizant way. The challenge is to understand how mutations stabilize different kinase configurations to alter function, and how this influences pathogenic potential of the kinase and its responses to therapeutic inhibitors. This goal is made more challenging by the complexity of the mutational landscape of diseases, and is further compounded by the conformational plasticity of each variant where multiple conformations coexist. We focus here on the human MEK1 kinase, a vital component of the RAS/MAPK pathway in which mutations cause cancers and developmental disorders called RASopathies. We sought to explore how these mutations alter the human MEK1 kinase at atomic resolution by utilizing enhanced sampling simulations and free energy calculations. We computationally mapped the different conformational stabilities of individual mutated systems by delineating the free energy landscapes, and showed how this relates directly to experimentally quantified developmental transformation potentials of the mutations. We conclude that mutations leverage variations in the hydrogen bonding network associated with the conformational plasticity to progressively stabilize the active-like conformational state of the kinase while destabilizing the inactive-like state. The mutations alter residue-level internal molecular correlations by differentially prioritizing different conformational states, delineating the various modes of MEK1 activation reminiscent of a gear-shifting mechanism. We define the molecular basis of conversion of this kinase from its inactive to its active state, connecting structure, dynamics, and function by delineating the energy landscape and conformational plasticity, thus augmenting our understanding of MEK1 regulation.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10872882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49688623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fluorescent biosensors illuminate the spatial regulation of cell signaling across scales. 荧光生物传感器阐明了跨尺度细胞信号的空间调节。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-10-31 DOI: 10.1042/BCJ20220223

Anne C Lyons, Sohum Mehta, Jin Zhang

引用次数: 0

Microrchidia 2/histone deacetylase 1 complex regulates E-cadherin gene expression and function. 小隐睾2/组蛋白脱乙酰酶1复合物调节E-钙粘蛋白基因的表达和功能。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-10-31 DOI: 10.1042/BCJ20230304

Liz Thomas, Namita Chutani, Krishna R, Asha S Nair, Nanda Kumar Yellapu, Prashanthi Karyala, Suresh B Pakala

{"title":"Microrchidia 2/histone deacetylase 1 complex regulates E-cadherin gene expression and function.","authors":"Liz Thomas, Namita Chutani, Krishna R, Asha S Nair, Nanda Kumar Yellapu, Prashanthi Karyala, Suresh B Pakala","doi":"10.1042/BCJ20230304","DOIUrl":"10.1042/BCJ20230304","url":null,"abstract":"Although Microrchidia 2 (MORC2) is widely overexpressed in human malignancies and linked to cancer cell proliferation, metabolism, and metastasis, the mechanism of action of MORC2 in cancer cell migration and invasion is yet undeciphered. Here, we identified for the first time that MORC2, a chromatin remodeler, regulates E-cadherin expression and, subsequently regulates breast cancer cell migration and invasion. We observed a negative correlation between the expression levels of MORC2 and E-cadherin in breast cancer. Furthermore, the overexpression of MORC2 resulted in decreased expression levels of E-cadherin. In addition, co-immunoprecipitation and chromatin immunoprecipitation assays revealed that MORC2 interacts with HDAC1 and gets recruited onto the E-cadherin promoter to inhibit its transcription, thereby suppress its expression. Consequently, knockdown of HDAC1 in MORC2-overexpressing cells led to reduced cancer cell migration and invasion. Interestingly, we noticed that MORC2-regulated glucose metabolism via c-Myc, and LDHA, also modulates the expression of E-cadherin. Collectively, these results demonstrate for the first time a mechanistic role for MORC2 as an upstream regulator of E-cadherin expression and its associated functions in breast cancer.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41181979","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

Comprehensive comparative assessment of the Arabidopsis thaliana MLO2-CALMODULIN2 interaction by various in vitro and in vivo protein-protein interaction assays. 通过各种体外和体内蛋白质-蛋白质相互作用测定对拟南芥MLO2-CALMODULIN2相互作用的综合比较评估。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2023-10-31 DOI: 10.1042/BCJ20230255

Kira von Bongartz, Björn Sabelleck, Anežka Baquero Forero, Hannah Kuhn, Franz Leissing, Ralph Panstruga

{"title":"Comprehensive comparative assessment of the Arabidopsis thaliana MLO2-CALMODULIN2 interaction by various in vitro and in vivo protein-protein interaction assays.","authors":"Kira von Bongartz, Björn Sabelleck, Anežka Baquero Forero, Hannah Kuhn, Franz Leissing, Ralph Panstruga","doi":"10.1042/BCJ20230255","DOIUrl":"10.1042/BCJ20230255","url":null,"abstract":"Mildew resistance locus o (MLO) proteins are heptahelical integral membrane proteins of which some isoforms act as susceptibility factors for the powdery mildew pathogen. In many angiosperm plant species, loss-of-function mlo mutants confer durable broad-spectrum resistance against the fungal disease. Barley Mlo is known to interact via a cytosolic carboxyl-terminal domain with the intracellular calcium sensor calmodulin (CAM) in a calcium-dependent manner. Site-directed mutagenesis has revealed key amino acid residues in the barley Mlo calmodulin-binding domain (CAMBD) that, when mutated, affect the MLO-CAM association. We here tested the respective interaction between Arabidopsis thaliana MLO2 and CAM2 using seven different types of in vitro and in vivo protein-protein interaction assays. In each assay, we deployed a wild-type version of either the MLO2 carboxyl terminus (MLO2CT), harboring the CAMBD, or the MLO2 full-length protein and corresponding mutant variants in which two key residues within the CAMBD were substituted by non-functional amino acids. We focused in particular on the substitution of two hydrophobic amino acids (LW/RR mutant) and found in most protein-protein interaction experiments reduced binding of CAM2 to the corresponding MLO2/MLO2CT-LW/RR mutant variants in comparison with the respective wild-type versions. However, the Ura3-based yeast split-ubiquitin system and in planta bimolecular fluorescence complementation (BiFC) assays failed to indicate reduced CAM2 binding to the mutated CAMBD. Our data shed further light on the interaction of MLO and CAM proteins and provide a comprehensive comparative assessment of different types of protein-protein interaction assays with wild-type and mutant versions of an integral membrane protein.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1d/30/BCJ-480-1615.PMC10586775.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41106923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0