Journal of Biological Chemistry最新文献_第7页

The zymogenic form of SARS-CoV-2 main protease: A discrete target for drug discovery. SARS-CoV-2 主要蛋白酶的酶原形式：药物发现的离散目标

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-13 DOI: 10.1016/j.jbc.2024.108079

Pavel Novotný, Jana Humpolíčková, Veronika Nováková, Stancho Stanchev, Kvido Stříšovský, Michala Zgarbová, Jan Weber, Robin Kryštůfek, Jana Starková, Martin Hradilek, Adéla Moravcová, Jana Günterová, Kathrin Bach, Pavel Majer, Jan Konvalinka, Taťána Majerová

{"title":"The zymogenic form of SARS-CoV-2 main protease: A discrete target for drug discovery.","authors":"Pavel Novotný, Jana Humpolíčková, Veronika Nováková, Stancho Stanchev, Kvido Stříšovský, Michala Zgarbová, Jan Weber, Robin Kryštůfek, Jana Starková, Martin Hradilek, Adéla Moravcová, Jana Günterová, Kathrin Bach, Pavel Majer, Jan Konvalinka, Taťána Majerová","doi":"10.1016/j.jbc.2024.108079","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108079","url":null,"abstract":"SARS-CoV-2 main protease (Mpro) autocatalytically releases itself out of the viral polyprotein to form a fully active mature dimer in a manner that is not fully understood. Here, we introduce several tools to help elucidate differences between cis (intramolecular) and trans (intermolecular) proteolytic processing and to evaluate inhibition of precursor Mpro. We found that many mutations at the P1 position of the N-terminal autoprocessing site do not block cis autoprocessing but do inhibit trans processing. Notably, substituting the wild-type glutamine at the P1 position with isoleucine retains Mpro in an unprocessed precursor form that can be purified and further studied. We also developed a cell-based reporter assay suitable for compound library screening and evaluation in HEK293T cells. This assay can detect both overall Mpro inhibition and the fraction of uncleaved preMpro through separable fluorescent signals. We observed that inhibitory compounds preferentially block mature Mpro. Bofutrelvir and a novel compound designed in-house showed the lowest selectivity between precursor and mature Mpro, indicating that inhibition of both forms may be possible. Additionally, we observed positive modulation of precursor activity at low concentrations of inhibitors. Our findings help expand understanding of the SARS-CoV-2 viral life cycle and may facilitate development of strategies to target preMpro for inhibition or premature activation of Mpro.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108079"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

An SH3-binding allosteric modulator stabilizes the global conformation of the AML-associated Src-family kinase, Hck.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-13 DOI: 10.1016/j.jbc.2024.108088

Ari M Selzer, Gabriella Gerlach, Giancarlo Gonzalez-Areizaga, Thomas E Wales, Stephanie Y Cui, Prema Iyer, John R Engen, Carlos Camacho, Rieko Ishima, Thomas E Smithgall

{"title":"An SH3-binding allosteric modulator stabilizes the global conformation of the AML-associated Src-family kinase, Hck.","authors":"Ari M Selzer, Gabriella Gerlach, Giancarlo Gonzalez-Areizaga, Thomas E Wales, Stephanie Y Cui, Prema Iyer, John R Engen, Carlos Camacho, Rieko Ishima, Thomas E Smithgall","doi":"10.1016/j.jbc.2024.108088","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108088","url":null,"abstract":"While ATP-site inhibitors for protein-tyrosine kinases are often effective drugs, their clinical utility can be limited by off-target activity and acquired resistance mutations due to the conserved nature of the ATP-binding site. However, combining ATP-site and allosteric kinase inhibitors can overcome these shortcomings in a double-drugging framework. Here we explored the allosteric effects of two pyrimidine diamines, PDA1 and PDA2, on the conformational dynamics and activity of the Src-family tyrosine kinase Hck, a promising drug target for acute myeloid leukemia. Using 1H-15N HSQC NMR, we mapped the binding site for both analogs to the SH3 domain. Despite the shared binding site, PDA1 and PDA2 had opposing effects on near-full-length Hck dynamics by hydrogen-deuterium exchange mass spectrometry, with PDA1 stabilizing and PDA2 disrupting the overall kinase conformation. Kinase activity assays were consistent with these observations, with PDA2 enhancing kinase activity while PDA1 was without effect. Molecular dynamics simulations predicted selective bridging of the kinase domain N-lobe and SH3 domain by PDA1, a mechanism of allosteric stabilization supported by site-directed mutagenesis of N-lobe contact sites. Cellular thermal shift assays confirmed SH3 domain-dependent interaction of PDA1 with wild-type Hck in myeloid leukemia cells and with a kinase domain gatekeeper mutant (T338M). These results identify PDA1 as a starting point for Src-family kinase allosteric inhibitor development that may work in concert with ATP-site inhibitors to suppress the evolution of resistance.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108088"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

New insights in uranium bioremediation by cytochromes of the bacterium G. uraniireducens.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-13 DOI: 10.1016/j.jbc.2024.108090

Alexandre Almeida, David L Turner, Marta A Silva, Carlos A Salgueiro

{"title":"New insights in uranium bioremediation by cytochromes of the bacterium G. uraniireducens.","authors":"Alexandre Almeida, David L Turner, Marta A Silva, Carlos A Salgueiro","doi":"10.1016/j.jbc.2024.108090","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108090","url":null,"abstract":"The bacterium Geotalea uraniireducens, commonly found in uranium-contaminated environments, plays a key role in bioremediation strategies by converting the soluble hexavalent form of uranium (UVI) into less soluble forms (e.g. UIV.). While most of the reduction and concomitant precipitation of uranium occur outside the cells, there have been reports of important reduction processes taking place in the periplasm. In any case, the triheme periplasmic cytochromes are crucial players, either by ensuring an effective interface between the cell´s interior and exterior or by directly participating in the reduction of the metal. Therefore, understanding the functional mechanism of the highly abundant G. uraniireducens' triheme cytochromes is crucial to assist the elucidation on the respiratory pathways in this bacterium. In this work, a detailed functional characterization of the triheme cytochromes PpcA and PpcB from G. uraniireducens was conducted using NMR and visible spectroscopy techniques. Despite sharing high amino acid sequence and structural homology with their counterparts from G. sulfurreducens, the results obtained showed that the heme reduction potential values are less negative, the order of oxidation of the hemes is distinct, and the redox and redox-Bohr network of interactions revealed unprecedented functional mechanisms of the G. uraniireducens cytochromes. In these cytochromes, the reduction potential values of the three heme groups are much more similar, hence covering a narrow range of values, features that facilitate the directional electron flow from the inner membrane, thereby favouring the optimal reduction of uranium.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108090"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response. 反式高尔基区域的 PI4P 失调激活了哺乳动物的高尔基应激反应。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-13 DOI: 10.1016/j.jbc.2024.108075

Kanae Sasaki, Marika Toide, Takuya Adachi, Fumi Morishita, Yuto Watanabe, Hajime Tajima Sakurai, Sadao Wakabayashi, Satoshi Kusumi, Toshiyuki Yamaji, Kaori Sakurai, Daisuke Koga, Kentaro Hanada, Masafumi Yohda, Hiderou Yoshida

{"title":"Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response.","authors":"Kanae Sasaki, Marika Toide, Takuya Adachi, Fumi Morishita, Yuto Watanabe, Hajime Tajima Sakurai, Sadao Wakabayashi, Satoshi Kusumi, Toshiyuki Yamaji, Kaori Sakurai, Daisuke Koga, Kentaro Hanada, Masafumi Yohda, Hiderou Yoshida","doi":"10.1016/j.jbc.2024.108075","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108075","url":null,"abstract":"The Golgi stress response is an important cytoprotective system that enhances Golgi function in response to cellular demand, while cells damaged by prolonged Golgi stress undergo cell death. OSW-1, a natural compound with anticancer activity, potently inhibits OSBP that transports cholesterol and phosphatidylinositol-4-phosphate (PI4P) at contact sites between the endoplasmic reticulum and the Golgi apparatus. Previously, we reported that OSW-1 induces the Golgi stress response, resulting in Golgi stress-induced transcription and cell death. However, the underlying molecular mechanism has been unknown. To reveal the mechanism of a novel pathway of the Golgi stress response regulating transcriptional induction and cell death (the PI4P pathway), we performed a genome-wide knockout screen and found that transcriptional induction as well as cell death induced by OSW-1 was repressed by the loss of regulators of PI4P synthesis, such as PITPNB and PI4KB. Our data indicate that OSW-1 induces Golgi stress-dependent transcriptional induction and cell death through dysregulation of the PI4P metabolism in the Golgi.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108075"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Crucial role and conservation of the three [2Fe-2S] clusters in the human mitochondrial ribosome. 人类线粒体核糖体中三个[2Fe-2S]簇的关键作用和保护。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-13 DOI: 10.1016/j.jbc.2024.108087

Linda Boß, Oliver Stehling, Hans-Peter Elsässer, Roland Lill

{"title":"Crucial role and conservation of the three [2Fe-2S] clusters in the human mitochondrial ribosome.","authors":"Linda Boß, Oliver Stehling, Hans-Peter Elsässer, Roland Lill","doi":"10.1016/j.jbc.2024.108087","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108087","url":null,"abstract":"Mitochondria synthesize only a small set of their proteins on endogenous mitoribosomes. These particles differ in structure and composition from both their bacterial 70S ancestors and cytosolic 80S ribosomes. Recently published high resolution structures of the human mitoribosome revealed the presence of three [2Fe-2S] clusters in the small and large subunits. Each of these clusters is coordinated in a bridging fashion by cysteine residues from two different mitoribosomal proteins. Here, we investigated the cell biological and biochemical roles of all three Fe/S clusters in mitochondrial function and assembly. First, we found a requirement of both early and late factors of the mitochondrial iron-sulfur cluster assembly machinery for protein translation indicating that not only the mitoribosome [2Fe-2S] clusters but also the [4Fe-4S] cluster of the mitoribosome assembly factor METTL17 are required for mitochondrial translation. Second, siRNA-mediated depletion of the cluster-coordinating ribosomal proteins bS18m, mS25 or mL66 and complementation with either the respective wild-type or cysteine-exchange proteins unveiled the importance of the clusters for assembly, stability, and function of the human mitoribosome. As a consequence, the lack of cluster binding to mitoribosomes impaired the activity of the mitochondrial respiratory chain complexes and led to altered mitochondrial morphology with a loss of cristae membranes. Finally, in silico investigation of the phylogenetic distribution of the cluster-coordinating cysteine motifs indicated their presence in most metazoan mitoribosomes, with exception of ray-finned fish. Collectively, our study highlights the functional need of mitochondrial Fe/S protein biogenesis for both protein translation and respiratory energy supply in most metazoan mitochondria.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108087"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Inhibition of L-Threonine Dehydrogenase from Trypanosoma cruzi reduces glycine and acetate production and interferes with parasite growth and viability. 抑制克氏锥虫的 L-苏氨酸脱氢酶可减少甘氨酸和醋酸的产生，并干扰寄生虫的生长和活力。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-13 DOI: 10.1016/j.jbc.2024.108080

Jessica do Nascimento Faria, Amanda G Eufrásio, Michelle Fagundes, Angel Lobo-Rojas, Letícia Marchese, Caio Cesar de Lima Silva, Eduardo H S Bezerra, Gustavo F Mercaldi, Marcos R Alborghetti, Mauricio L Sforca, Artur T Cordeiro

{"title":"Inhibition of L-Threonine Dehydrogenase from Trypanosoma cruzi reduces glycine and acetate production and interferes with parasite growth and viability.","authors":"Jessica do Nascimento Faria, Amanda G Eufrásio, Michelle Fagundes, Angel Lobo-Rojas, Letícia Marchese, Caio Cesar de Lima Silva, Eduardo H S Bezerra, Gustavo F Mercaldi, Marcos R Alborghetti, Mauricio L Sforca, Artur T Cordeiro","doi":"10.1016/j.jbc.2024.108080","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108080","url":null,"abstract":"Trypanosoma cruzi is a flagellated protozoan and the etiological agent of Chagas Disease, a neglected tropical disease described by Carlos Chagas in 1909 that remains without appropriate diagnostics and treatment. Throughout its life cycle, T. cruzi undergoes through many different environments, requiring adaptation of its metabolism to different nutrition sources. Recent studies have confirmed the adaptability of T. cruzi metabolism to different carbon sources and encouraged a deeper investigation of related metabolic pathways. In the present study, we investigated the catabolism of threonine in T. cruzi epimastigotes cultivated in LIT medium and following 24h of starvation in PBS. In LIT medium, threonine, serine and histidine were rapidly consumed concomitantly with carbohydrates during parasite exponential growth. When threonine was provided as the only carbon source to starved parasites, they excreted acetate and glycine, corroborating the activity of a mitochondrial threonine degradation pathway. Subsequently, we used a recombinant T. cruzi L-threonine dehydrogrenase (TcTDH) to screen the ChagasBox, an open-source collection of phenotypic hits and identified compound TCMDC-143160 as a low micromolar TcTDH inhibitor (IC50 = 3.5 μM). When TCDMC-143160 was administrated to starved parasites, it inhibited the threonine degradation pathway. Finally, we report the crystal structure of TcTDH and characterize its allosteric activation by potassium. Collectively, these data demonstrate the relevance of threonine catabolism in T. cruzi metabolism and provide a set of tools to further investigate TcTDH as a potential drug target for Chagas disease.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108080"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Phase Partitioning of the Neutrophil Oxidative Burst is Coordinated by Accessory Pathways of Glucose Metabolism and Mitochondrial Activity. 中性粒细胞氧化爆发的阶段划分由葡萄糖代谢和线粒体活动的辅助途径协调

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-13 DOI: 10.1016/j.jbc.2024.108091

Tyler Jobe, Jonah Stephan, Collin K Wells, Maleesha De Silva, Pawel K Lorkiewicz, Bradford G Hill, Marcin Wysoczynski

{"title":"Phase Partitioning of the Neutrophil Oxidative Burst is Coordinated by Accessory Pathways of Glucose Metabolism and Mitochondrial Activity.","authors":"Tyler Jobe, Jonah Stephan, Collin K Wells, Maleesha De Silva, Pawel K Lorkiewicz, Bradford G Hill, Marcin Wysoczynski","doi":"10.1016/j.jbc.2024.108091","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108091","url":null,"abstract":"Neutrophils are a part of the innate immune system and produce reactive oxygen species (ROS) to extinguish pathogens. The major source of ROS in neutrophils is NADPH oxidase, which is fueled by NADPH generated via the pentose phosphate pathway; however, it is unclear how other accessory glucose metabolism pathways and mitochondrial activity influence the respiratory burst. We examined the temporal dynamics of the respiratory burst and delineated how metabolism changes over time after neutrophil activation. Bone marrow-derived neutrophils were stimulated with phorbol 12-myristate 13-acetate (PMA), and the respiratory burst was measured via extracellular flux analysis. Metabolomics experiments utilizing 13C6-glucose highlighted the activation of glycolysis as well as ancillary pathways of glucose metabolism in activated neutrophils. PMA stimulation acutely increased 13C enrichment into glycerol 3-phosphate (G3P) and citrate, whereas increases in 13C enrichment in the glycogen intermediate, UDP-hexose, and end products of the hexosamine and serine biosynthetic pathways occurred only during the late phase of the oxidative burst. Targeted inhibition of the G3P shuttle, glycogenolysis, serine biosynthesis, and mitochondrial respiration demonstrated that the G3P shuttle contributes to the general magnitude of ROS production; that glycogen contributes solely to the early respiratory burst; and that the serine biosynthetic pathway activity and Complex III-driven mitochondrial activity influence respiratory burst duration. Collectively, these results show that the neutrophil oxidative burst is highly dynamic, with coordinated changes in metabolism that control the initiation, magnitude, and duration of ROS production.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108091"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

CspZ variant-specific interaction with Factor H incorporates a metal site to support Lyme borreliae complement evasion. CspZ变体与因子H的特异性相互作用结合了一个金属位点，支持莱姆包虫病补体规避。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-13 DOI: 10.1016/j.jbc.2024.108083

Kalvis Brangulis, Valerie Sürth, Ashley L Marcinkiewicz, Inara Akopjana, Andris Kazaks, Janis Bogans, Alisa Huber, Yi-Pin Lin, Peter Kraiczy

{"title":"CspZ variant-specific interaction with Factor H incorporates a metal site to support Lyme borreliae complement evasion.","authors":"Kalvis Brangulis, Valerie Sürth, Ashley L Marcinkiewicz, Inara Akopjana, Andris Kazaks, Janis Bogans, Alisa Huber, Yi-Pin Lin, Peter Kraiczy","doi":"10.1016/j.jbc.2024.108083","DOIUrl":"10.1016/j.jbc.2024.108083","url":null,"abstract":"Polymorphic microbial immune evasion proteins dictate the pathogen species- or strain-specific virulence. Metals can impact how microbial proteins confer host-pathogen interactions, but whether this activity can be allelically variable is unclear. Here, we investigate the polymorphic CspZ protein of Lyme disease (LD) spirochete bacteria to assess the role of metals in protein-protein interaction. CspZ facilitates evasion of the complement system, the first-line of immune defense through binding to the complement regulator Factor H (FH). By obtaining a high-resolution co-crystal CspZ-FH structure, we identified a zinc coordinating the binding of FH SCR6-7 domains to a Glu65 on a loop from CspZ of B. burgdorferi B31. However, zinc is dispensable for human FH binding for CspZ orthologs with a different loop orientation and/or lacking this glutamate. Phylogenetic analysis of all known human FH binding CspZ variants further grouped the proteins into three unique lineages correlating with loop sequences. This suggests multiple FH-binding mechanisms evolved through LD spirochete-host interactions. Overall, this multidisciplinary work elucidates how the allelically-specific immune evasion role of metals is impacted by microbial protein polymorphisms.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108083"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Epigenetic activation of JAG1 by AID contributes to metastasis of hepatocellular carcinoma.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-13 DOI: 10.1016/j.jbc.2024.108078

Junna Jiao, Kun Shao, Zixian Liu, Lulu Liu, Ziru Nie, Jinhua Wu, Xiaoyu Shi, Ruihan Wang, Zhuang Qian, Angang Yang, Zhuangwei Lv

{"title":"Epigenetic activation of JAG1 by AID contributes to metastasis of hepatocellular carcinoma.","authors":"Junna Jiao, Kun Shao, Zixian Liu, Lulu Liu, Ziru Nie, Jinhua Wu, Xiaoyu Shi, Ruihan Wang, Zhuang Qian, Angang Yang, Zhuangwei Lv","doi":"10.1016/j.jbc.2024.108078","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108078","url":null,"abstract":"Metastasis is a major cause of fatality in hepatocellular carcinoma (HCC), although the precise mechanisms driving the metastatic process remain incompletely understood. In this study, we have made several important findings. Firstly, we have discovered that elevated activation-induced cytidine deaminase (AID) expression is positively correlated with Jagged 1 (JAG1) levels in clinically metastatic HCC patients. Moreover, we observed that depletion of either AID or JAG1 leads to a reduction in HCC metastasis. Secondly, we have identified AID acts as a transcriptional regulator that regulates JAG1 transcription by interacting with histone acetyltransferase 1 (HAT1) in metastatic HCC cells. Furthermore, our results demonstrate that any domains of AID can cooperate with HAT1 to enhance JAG1 transcription. Importantly, we have determined that the AID/HAT1 complex directly binds to specific regions within the JAG1 gene body, specifically -1.504 kb to -1.104 kb region, thereby influencing the epigenetic state of the JAG1 promoter through modulating histone methylation, histone acetylation and DNA methylation. Furthermore, we have elucidated that the AID-JAG1/NOTCH-c-FOS axis plays a pivotal role in facilitating HCC metastasis. Consequently, the inhibitory effects of MG149 on both AID and JAG1 significantly mitigate the progression of HCC. This investigation uncovers a heretofore unappreciated function of AID as a transcriptional regulator in the metastasis of HCC, heralding a promising therapeutic approach.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108078"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Inhibition of the neddylation E2 enzyme UBE2M in macrophages protects against E. coli-induced sepsis.

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-12-13 DOI: 10.1016/j.jbc.2024.108085

Xuehuan Wen, Songjie Bai, Guirun Xiong, Huiqing Xiu, Jiahui Li, Jie Yang, Qing Yu, Bingyu Li, Ruomeng Hu, Lanxin Cao, Zhijian Cai, Shufang Zhang, Gensheng Zhang

{"title":"Inhibition of the neddylation E2 enzyme UBE2M in macrophages protects against E. coli-induced sepsis.","authors":"Xuehuan Wen, Songjie Bai, Guirun Xiong, Huiqing Xiu, Jiahui Li, Jie Yang, Qing Yu, Bingyu Li, Ruomeng Hu, Lanxin Cao, Zhijian Cai, Shufang Zhang, Gensheng Zhang","doi":"10.1016/j.jbc.2024.108085","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.108085","url":null,"abstract":"UBE2M, an essential neddylation E2 enzyme, has been implicated in the pathogenesis of various diseases, including cancers, viral infections, and obesity. However, whether UBE2M is involved in the pathogenesis of bacterial sepsis remains unclear. In an Escherichia coli (E. coli)-induced sepsis mouse model, increased UBE2M expression in macrophages in liver and lung tissues postinfection was observed. To further clarify the role of UBE2M in macrophages, mice with macrophage-specific deletion of UBE2M (Lysm+Ube2mf/f) were constructed. Compared with control mice, these mice presented decreased levels of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α; reduced sepsis-induced organ damage; and improved survival. Notably, macrophage-specific deletion of UBE2M did not impair E. coli clearance. In vitro experiments also revealed that UBE2M-deficient macrophages produced fewer proinflammatory cytokines after E. coli infection without hindering E. coli clearance. RNA-sequencing analysis revealed that UBE2M deletion in macrophages after LPS stimulation notably suppressed transcriptional activation within the JAK-STAT and Toll-like receptor signaling pathways, which was further confirmed by gene set enrichment analysis. Additionally, Western blotting results confirmed that UBE2M deletion inhibited the activation of the NF-κB, ERK, and JAK-STAT signaling pathways. In conclusion, our findings indicate that specific deletion of UBE2M in macrophages protects against E. coli-induced sepsis by downregulating the excessive inflammatory response, potentially providing a novel strategy against sepsis by targeting UBE2M.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"108085"},"PeriodicalIF":4.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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