Journal of Biological Chemistry最新文献_第7页

PP2A activation overcomes leptomeningeal dissemination in Group 3 medulloblastoma. PP2A 激活克服了第 3 组髓母细胞瘤的脑膜扩散。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-15 DOI: 10.1016/j.jbc.2024.107892

Nazia Nazam,Michael H Erwin,Janet R Julson,Colin H Quinn,Andee M Beierle,Laura V Bownes,Jerry E Stewart,Kyung-Don Kang,Swatika Butey,Elizabeth Mroczek-Musulman,Michael Ohlmeyer,Elizabeth A Beierle

{"title":"PP2A activation overcomes leptomeningeal dissemination in Group 3 medulloblastoma.","authors":"Nazia Nazam,Michael H Erwin,Janet R Julson,Colin H Quinn,Andee M Beierle,Laura V Bownes,Jerry E Stewart,Kyung-Don Kang,Swatika Butey,Elizabeth Mroczek-Musulman,Michael Ohlmeyer,Elizabeth A Beierle","doi":"10.1016/j.jbc.2024.107892","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107892","url":null,"abstract":"Leptomeningeal dissemination (LMD) is the primary cause of treatment failure in children with Group 3 medulloblastoma (MB). Building on our previous work on protein phosphatase 2A (PP2A) activation in MB, here we present pre-clinical and molecular data on the effects of two novel classes of PP2A activators on disease processes of LMD in Group 3 MB. The PP2A activators employed in this study are ATUX-6156 and ATUX-6954 (diarylmethylcycloamine sulfonylureas), and ATUX-1215 and ATUX-5800 (diarylmethyl-4-aminotetrahydropyran-sulfonamides). Treatment with these compounds led to suppression of the endogenous PP2A inhibitor, cancerous inhibitor of PP2A (CIP2A), enhanced phosphatase activity (10-60%), and reduced MB viability, migration, and invasion, prerequisites for MB cells to access the cerebrospinal fluid, affecting the initiation stage of LMD. PP2A activator treatment of MB cells led to apoptosis mediated via caspase 9/PARP signaling due to decreased phosphorylation of Bad, impeding the dispersal stage of LMD. Cell proliferation and LMD-driving cellular traits and molecules pertinent to the third stage, colonization, were also affected. Treatment with ATUX-1215 or ATUX-5800 prevented LMD in an intraventricular murine model of MB, possibly mediated by disruption of the CCL2-CCR2 axis by altered NF-kB phosphorylation via disrupted AKT signaling. The present investigation offers proof-of-principle data for PP2A-based reactivation therapy for Group 3 MB and provides the first indications that PP2A reactivation may challenge the current paradigm in targeting the 3-stage process of MB LMD. Further investigations of PP2A activators are warranted as these compounds may prove beneficial as therapeutics for MB.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449241","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

Oncogenic accumulation of cysteine promotes cancer cell proliferation by regulating the translation of D-type cyclins. 半胱氨酸的致癌积累通过调节 D 型细胞周期蛋白的翻译来促进癌细胞增殖。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-14 DOI: 10.1016/j.jbc.2024.107890

Yumi Okano,Tomoaki Yamauchi,Runa Fukuzaki,Akito Tsuruta,Yuya Yoshida,Yuya Tsurudome,Kentaro Ushijima,Naoya Matsunaga,Satoru Koyanagi,Shigehiro Ohdo

{"title":"Oncogenic accumulation of cysteine promotes cancer cell proliferation by regulating the translation of D-type cyclins.","authors":"Yumi Okano,Tomoaki Yamauchi,Runa Fukuzaki,Akito Tsuruta,Yuya Yoshida,Yuya Tsurudome,Kentaro Ushijima,Naoya Matsunaga,Satoru Koyanagi,Shigehiro Ohdo","doi":"10.1016/j.jbc.2024.107890","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107890","url":null,"abstract":"Malignant cells exhibit a high demand for amino acids to sustain their abnormal proliferation. Particularly, the intracellular accumulation of cysteine is often observed in cancer cells. Previous studies have shown that deprivation of intracellular cysteine in cancer cells results in the accumulation of lipid peroxides in the plasma membrane and induction of ferroptotic cell death, indicating that cysteine plays a critical role in the suppression of ferroptosis. Herein, we found that the oncogenic accumulation of cysteine also contributes to cancer cell proliferation by promoting the cell cycle progression, which is independent of its suppressive effect on ferroptosis. The growth ability of four types of cancer cells, including murine hepatocarcinoma cells, but not of primary hepatocytes, were dependent on the exogenous supply of cysteine. Deprivation of intracellular cysteine in cancer cells induced cell cycle arrest at the G0/G1 phase, accompanied by a decrease in the expression of cyclin D1 and D2 proteins. The cysteine deprivation-induced decrease in D-type cyclin expression was associated with the upregulation of eukaryotic translation initiation factor 4E binding protein (4E-BP1), which represses the translation of cyclin D1 and D2 proteins by binding to eukaryotic translation initiation factor 4E (eIF4E). Similar results were observed in hepatocarcinoma cells treated with erastin, an xCT inhibitor. These findings reveal an unappreciated role of cysteine in regulating the growth of malignant cancer cells and deepen our understanding of the cytotoxic effect of xCT inhibitor to prevent cancer cell proliferation.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447994","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

The highly conserved region within exonuclease III-like in PML-I regulates the cytoplasmic localization of PML-NBs. PML-I 中类似于 III 号外切酶的高度保守区域调节 PML-NBs 的细胞质定位。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-10 DOI: 10.1016/j.jbc.2024.107872

Xinxin Liang,Jinwen Chen,Peijie Yan,Zhongzhou Chen,Chao Gao,Rulan Bai,Jun Tang

{"title":"The highly conserved region within exonuclease III-like in PML-I regulates the cytoplasmic localization of PML-NBs.","authors":"Xinxin Liang,Jinwen Chen,Peijie Yan,Zhongzhou Chen,Chao Gao,Rulan Bai,Jun Tang","doi":"10.1016/j.jbc.2024.107872","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107872","url":null,"abstract":"The sub-nuclear protein structure PML-NB regulates a wide range of important cellular functions, while its abnormal cytoplasmic localization may have pathological consequences. However, the nature of this aberrant localization remains poorly understood. In this study, we unveil that PML-I, the most conserved and abundant structural protein of PML-NB, possesses potent cytoplasmic targeting ability within the N-terminal half of the exonuclease III-like domain encoded by its unique exon 9, independent of the known nuclear localization signal. Fusion of this region to PML-VI can relocate PML-VI from the nucleus to the cytosol. Structural and deletion analysis revealed that the cytoplasmic targeting ability of this domain was restrained by the sequences encoded by exon 8a and the 3' portion of exon 9 in PML-I. Deletion of either of these regions relocates PML-I to the cytosol. Furthermore, we observed a potential interaction between the ER-localized TREX1 and the cytoplasmic-located PML-I mutants. Our results suggest that perturbation of the EXO-like domain of PML-I may represent an important mode to translocate PMLs from the nucleus to the cytosol, thereby interfering with the normal nuclear functions of PML-NBs.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431144","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

Type I interferon signaling and peroxisomal dysfunction contribute to enhanced inflammatory cytokine production in Irgm1-deficient macrophages. I型干扰素信号传导和过氧化物酶体功能障碍导致Irgm1缺陷的巨噬细胞产生更多炎症细胞因子。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-10 DOI: 10.1016/j.jbc.2024.107883

Brian E Fee,Lanette R Fee,Mark Menechella,Bethann Affeldt,Aemilia R Sprouse,Amina Bounini,Yazan Alwarawrah,Caitlyn T Molloy,Olga R Ilkayeva,Joseph A Prinz,Devi Swain Lenz,Nancie J MacIver,Prashant Rai,Michael B Fessler,Jörn Coers,Gregory A Taylor

{"title":"Type I interferon signaling and peroxisomal dysfunction contribute to enhanced inflammatory cytokine production in Irgm1-deficient macrophages.","authors":"Brian E Fee,Lanette R Fee,Mark Menechella,Bethann Affeldt,Aemilia R Sprouse,Amina Bounini,Yazan Alwarawrah,Caitlyn T Molloy,Olga R Ilkayeva,Joseph A Prinz,Devi Swain Lenz,Nancie J MacIver,Prashant Rai,Michael B Fessler,Jörn Coers,Gregory A Taylor","doi":"10.1016/j.jbc.2024.107883","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107883","url":null,"abstract":"The human IRGM gene has been linked to inflammatory diseases including sepsis and Crohn's disease. Decreased expression of human IRGM, or of the mouse orthologues Irgm1 and Irgm2, leads to increased production of a number of inflammatory chemokines and cytokines in vivo and/or in cultured macrophages. Prior work has indicated that increased cytokine production is instigated by metabolic alterations and by changes in mitochondrial homeostasis; however, a comprehensive mechanism has not been elucidated. In the studies presented here, RNA deep sequencing and quantitative PCR were used to show that increases in cytokine production, as well as most changes in the transcriptional profile of Irgm1-/- bone marrow-derived macrophages (BMM), are dependent on increased type I IFN production seen in those cells. Metabolic alterations that drive increased cytokines in Irgm1-/- BMM - specifically increases in glycolysis and increased accumulation of acyl-carnitines - were unaffected by quenching type I IFN signaling. Dysregulation of peroxisomal homeostasis was identified as a novel upstream pathway that governs type I IFN production and inflammatory cytokine production. Collectively, these results enhance our understanding of the complex biochemical changes that are triggered by lack of Irgm1 and contribute to inflammatory disease seen with Irgm1-deficiency.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431145","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

Polypurine Reverse Hoogsteen hairpins as a therapeutic tool for SARS-CoV-2 infection. 聚嘌呤反向胡格斯泰因发夹作为治疗 SARS-CoV-2 感染的工具。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-10 DOI: 10.1016/j.jbc.2024.107884

Carlos J Ciudad,Simonas Valiuska,José Manuel Rojas,Pablo Nogales-Altozano,Anna Aviñó,Ramón Eritja,Miguel Chillón,Noemí Sevilla,Verónique Noé

{"title":"Polypurine Reverse Hoogsteen hairpins as a therapeutic tool for SARS-CoV-2 infection.","authors":"Carlos J Ciudad,Simonas Valiuska,José Manuel Rojas,Pablo Nogales-Altozano,Anna Aviñó,Ramón Eritja,Miguel Chillón,Noemí Sevilla,Verónique Noé","doi":"10.1016/j.jbc.2024.107884","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107884","url":null,"abstract":"Although COVID-19 pandemic was declared no longer a global emergency by the World Health Organization in May 2023, SARS-CoV-2 is still infecting people across the world. Many therapeutic oligonucleotides such as ASOs, siRNAs or CRISPR-based systems emerged as promising antiviral strategies for the treatment of SARS-CoV-2. In this work we explored the inhibitory potential on SARS-CoV-2 replication of Polypurine Reverse Hoogsteen Hairpins (PPRHs), CC1-PPRH and CC3-PPRH, targeting specific polypyrimidine sequences within the replicase and Spike regions, respectively, and previously validated for COVID-19 diagnosis. Both PPRHs bound to their target sequences in the viral genome with high affinity in the order of nM. In vitro, both PPRHs reduced viral replication by more than 92% when transfected into VERO-E6 cells 24 hours prior infection with SARS-CoV-2. In vivo intranasal administration of CC1-PPRH in K18-hACE2 mice expressing the human ACE receptor protected all the animals from SARS-CoV-2 infection. The properties of PPRHs position them as promising candidates for the development of novel therapeutics against SARS-CoV-2 and other viral infections.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431146","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

CDK-Dependent Phosphorylation Regulates PNKP Function in DNA Replication. CDK 依赖性磷酸化调控 PNKP 在 DNA 复制中的功能

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-10 DOI: 10.1016/j.jbc.2024.107880

Fatemeh Mashayekhi,Elham Zeinali,Cassandra Ganje,Mesfin Fanta,Lei Li,Roseline Godbout,Michael Weinfeld,Ismail Hassan Ismail

{"title":"CDK-Dependent Phosphorylation Regulates PNKP Function in DNA Replication.","authors":"Fatemeh Mashayekhi,Elham Zeinali,Cassandra Ganje,Mesfin Fanta,Lei Li,Roseline Godbout,Michael Weinfeld,Ismail Hassan Ismail","doi":"10.1016/j.jbc.2024.107880","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107880","url":null,"abstract":"Okazaki fragment maturation (OFM) stands as a pivotal DNA metabolic process, crucial for genome integrity and cell viability. Dysregulation of OFM leads to DNA single-strand breaks- accumulation, which is linked to various human diseases such as cancer and neurodegenerative disorders. Recent studies have implicated LIG3-XRCC1 acting in an alternative OFM pathway to the canonical FEN1-LIG1 pathway. Here, we reveal that polynucleotide kinase-phosphatase (PNKP) is another key participant in DNA replication, akin to LIG3-XRCC1. Through functional experiments, we demonstrate PNKP's enrichment at DNA replication forks and its association with PCNA, indicating its involvement in replication processes. Cellular depletion of PNKP mirrors defects observed in OFM-related proteins, highlighting its significance in replication fork dynamics. Additionally, we identify PNKP as a substrate for cyclin-dependent kinase 1/2 (CDK1/2), which phosphorylates PNKP at multiple residues. Mutation analysis of these phosphorylation sites underscores the importance of CDK2-mediated PNKP phosphorylation in DNA replication. Our findings collectively indicate a novel role for PNKP in facilitating Okazaki fragment joining, thus shedding light on its contribution to genome stability maintenance.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431147","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

α-Amino-β-Carboxymuconate-ε-Semialdehyde Decarboxylase Catalyzes Enol/Keto Tautomerization of Oxaloacetate. α-氨基-β-羧基琥珀酸-ε-半乳糖醛脱羧酶催化草酰乙酸的烯醇/酮共聚。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-10 DOI: 10.1016/j.jbc.2024.107878

Yu Yang,Ian Davis,Ryan A Altman,Aimin Liu

{"title":"α-Amino-β-Carboxymuconate-ε-Semialdehyde Decarboxylase Catalyzes Enol/Keto Tautomerization of Oxaloacetate.","authors":"Yu Yang,Ian Davis,Ryan A Altman,Aimin Liu","doi":"10.1016/j.jbc.2024.107878","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107878","url":null,"abstract":"ACMSD (α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase) is a key metalloenzyme critical for regulating de novo endogenous NAD+/NADH biosynthesis through the tryptophan-kynurenine pathway. This decarboxylase is a recognized target implicated in mitochondrial diseases and neurodegenerative disorders. However, unraveling its enzyme-substrate complex has been challenging due to its high catalytic efficiency. Here, we present a combined biochemical and structural study wherein we determined the crystal structure of ACMSD in complex with malonate. Our analysis revealed significant rearrangements in the active site, particularly in residues crucial for ACMS decarboxylation, including Arg51, Arg239* (a residue from an adjacent subunit), His228, and Trp194. Docking modeling studies proposed a putative ACMS binding mode. Additionally, we found that ACMSD catalyzes oxaloacetic acid (OAA) tautomerization at a rate of 6.51 ± 0.42 s-1 but not decarboxylation. The isomerase activity of ACMSD on OAA warrants further investigation in future biological studies. Subsequent mutagenesis studies and crystallographic analysis of W194A variant shed light on the roles of specific second-coordination sphere residues. Our findings indicate that Arg51 and Arg239* are crucial for OAA tautomerization. Moreover, our comparative analysis with related isomerase superfamily members underscores a general strategy employing arginine residues to promote OAA isomerization. Given the observed isomerase activity of ACMSD on OAA and its structural similarity to ACMS, we propose that ACMSD may facilitate isomerization to ensure ACMS is in the optimal tautomeric form for subsequent decarboxylation initiated by the zinc-bound hydroxide ion. Overall, these findings deepen the understanding of the structure and function of ACMSD, offering insights into potential therapeutic interventions.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431150","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

Transcriptome and proteome profiling reveals TREM2-dependent and -independent glial response and metabolic perturbation in an Alzheimer's mouse model. 转录组和蛋白质组分析揭示了阿尔茨海默氏症小鼠模型中依赖和不依赖 TREM2 的神经胶质反应和代谢紊乱。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-10 DOI: 10.1016/j.jbc.2024.107874

Da Lin,Sarah Kaye,Min Chen,Amogh Lyanna,Lihua Ye,Luke A Hammond,Jie Gao

{"title":"Transcriptome and proteome profiling reveals TREM2-dependent and -independent glial response and metabolic perturbation in an Alzheimer's mouse model.","authors":"Da Lin,Sarah Kaye,Min Chen,Amogh Lyanna,Lihua Ye,Luke A Hammond,Jie Gao","doi":"10.1016/j.jbc.2024.107874","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107874","url":null,"abstract":"Elucidating the intricate molecular mechanisms of Alzheimer's disease (AD) requires a multidimensional analysis incorporating various omics data. In this study, we employed transcriptome and proteome profiling of AppNL-G-F, a human APP knock-in model of amyloidosis, at the early and mid-stages of amyloid-beta (Aβ) pathology to delineate the impacts of Aβ deposition on brain cells. By contrasting AppNL-G-F mice with TREM2 (Triggering receptor expressed on myeloid cells 2) knockout models, our study further investigates the role of TREM2, a well-known AD risk gene, in influencing microglial responses to Aβ pathology. Our results highlight altered microglial states as a central feature of Aβ pathology, characterized by the significant upregulation of microglia-specific genes related to immune responses such as complement system and antigen presentation, and catabolic pathways such as phagosome formation and lysosome biogenesis. The absence of TREM2 markedly diminishes the induction of these genes, impairs Aβ clearance, and exacerbates dystrophic neurite formation. Importantly, TREM2 is required for the microglial engagement with Aβ plaques and the formation of compact Aβ plaque cores. Furthermore, this study reveals substantial disruptions in energy metabolism and protein synthesis, signaling a shift from anabolism to catabolism in response to Aβ deposition. This metabolic alteration, coupled with a decrease in synaptic protein abundance, occurs independently of TREM2, suggesting the direct effects of Aβ deposition on synaptic integrity and plasticity. In summary, our findings demonstrate altered microglial states and metabolic disruption following Aβ deposition, offering mechanistic insights into Aβ pathology and highlighting the potential of targeting these pathways in AD therapy.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431151","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

Site specific O-GlcNAcylation of progesterone receptor (PR) supports PR attenuation of interferon stimulated genes (ISGs) and tumor growth in breast cancer. 黄体酮受体（PR）的位点特异性 O-GlcNAcylation 支持 PR 对干扰素刺激基因（ISGs）和乳腺癌肿瘤生长的抑制作用。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-10 DOI: 10.1016/j.jbc.2024.107886

Harmony Saunders,Sean Holloran,Gloria Trinca,Antonio Artigues,Maite Villar,Julio Tinoco,Wagner Barbosa Dias,Lauryn Werner,Eilidh Chowanec,Amanda Heard,Prabhakar Chalise,Chad Slawson,Christy Hagan

{"title":"Site specific O-GlcNAcylation of progesterone receptor (PR) supports PR attenuation of interferon stimulated genes (ISGs) and tumor growth in breast cancer.","authors":"Harmony Saunders,Sean Holloran,Gloria Trinca,Antonio Artigues,Maite Villar,Julio Tinoco,Wagner Barbosa Dias,Lauryn Werner,Eilidh Chowanec,Amanda Heard,Prabhakar Chalise,Chad Slawson,Christy Hagan","doi":"10.1016/j.jbc.2024.107886","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107886","url":null,"abstract":"Hormone receptor (HR) positive breast cancer, defined by expression of estrogen (ER) and/or progesterone (PR) receptor expression, is the most commonly diagnosed type of breast cancer. PR alters the transcriptional landscape to support tumor growth in concert with or independent of ER. Thus, understanding the mechanisms regulating PR function are critical to developing new strategies to treat HR+ breast cancer. O-GlcNAc is a post-translational modification responsible for nutrient sensing that modulates protein function. Although PR is heavily post-translationally modified, through phosphorylation and O-GlcNAcylation, specific sites of O-GlcNAcylation on PR and how they regulate PR action, have not been investigated. Using established PR-expressing breast cancer cell lines, we mapped several sites of O-GlcNAcylation on PR. RNA-sequencing after PR O-GlcNAc site mutagenesis revealed site-specific O-GlcNAcylation of PR is critical for ligand-independent suppression of interferon signaling, a regulatory function of PR in breast cancer. Furthermore, O-GlcNAcylation of PR enhances PR-driven tumor growth in vivo. We have delineated one contributing mechanism to PR function in breast cancer that impacts tumor growth, and provided additional insight into the mechanism through which PR attenuates interferon signaling.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431159","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

O-GlcNAcylation of ribosome-associated proteins is concomitant with translational reprogramming during proteotoxic stress. 在蛋白毒性应激过程中，核糖体相关蛋白的 O-GlcNAcylation 与翻译重编程同时发生。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-10 DOI: 10.1016/j.jbc.2024.107877

Quira Zeidan,Jie L Tian,Junfeng Ma,Farzad Eslami,Gerald W Hart

{"title":"O-GlcNAcylation of ribosome-associated proteins is concomitant with translational reprogramming during proteotoxic stress.","authors":"Quira Zeidan,Jie L Tian,Junfeng Ma,Farzad Eslami,Gerald W Hart","doi":"10.1016/j.jbc.2024.107877","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107877","url":null,"abstract":"Protein O-GlcNAc modification, similar to phosphorylation, supports cell survival by regulating key processes like transcription, cell division, trafficking, signaling, and stress tolerance. However, its role in protein homeostasis, particularly in protein synthesis, folding, and degradation remains poorly understood. Our previous research shows that O-GlcNAc cycling enzymes associate with the translation machinery during protein synthesis and modify ribosomal proteins. Protein translation is closely linked to 26S proteasome activity, which recycles amino acids and clears misfolded proteins during stress, preventing aggregation and cell death. In this study, we demonstrate that pharmacological perturbation of the proteasome-like that used in cancer treatment- leads to the increased abundance of OGT and OGA in a ribosome-rich fraction, concurrent with O-GlcNAc modification of core translational and ribosome-associated proteins. This interaction is synchronous with eIF2α-dependent translational reprogramming. We also found that protein ubiquitination depends partly on O-GlcNAc metabolism in MEFs, as OGT-depleted cells show decreased ubiquitination under stress. Using an O-GlcNAc-peptide enrichment strategy followed by LC-MS/MS, we identified 84 unique O-GlcNAc sites across 55 proteins, including ribosomal proteins, nucleolar factors, and the 70-kDa heat shock protein family. Hsp70 and OGT colocalize with the translational machinery in an RNA-independent manner, aiding in partial protein translation recovery during sustained stress. O-GlcNAc cycling on ribosome-associated proteins collaborates with Hsp70 to restore protein synthesis during proteotoxicity, suggesting a role in tumor resistance to proteasome inhibitors.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431153","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