The Journal of Biological Chemistry最新文献_第8页

Metabolic reprogramming contributes to radioprotection by protein kinase Cδ. 代谢重编程有助于蛋白激酶Cδ的辐射保护。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-08-21 DOI: 10.1016/j.jbc.2023.105186

Angela M Ohm, Trisiani Affandi, Julie A Reisz, M Cecilia Caino, Angelo D'Alessandro, Mary E Reyland

{"title":"Metabolic reprogramming contributes to radioprotection by protein kinase Cδ.","authors":"Angela M Ohm, Trisiani Affandi, Julie A Reisz, M Cecilia Caino, Angelo D'Alessandro, Mary E Reyland","doi":"10.1016/j.jbc.2023.105186","DOIUrl":"10.1016/j.jbc.2023.105186","url":null,"abstract":"Loss of protein kinase Cδ (PKCδ) activity renders cells resistant to DNA damaging agents, including irradiation; however, the mechanism(s) underlying resistance is poorly understood. Here, we have asked if metabolic reprogramming by PKCδ contributes to radioprotection. Analysis of global metabolomics showed that depletion of PKCδ affects metabolic pathways that control energy production and antioxidant, nucleotide, and amino acid biosynthesis. Increased NADPH and nucleotide production in PKCδ-depleted cells is associated with upregulation of the pentose phosphate pathway (PPP) as evidenced by increased activation of G6PD and an increase in the nucleotide precursor, 5-phosphoribosyl-1-pyrophosphate. Stable isotope tracing with U-[13C6] glucose showed reduced utilization of glucose for glycolysis in PKCδ-depleted cells and no increase in U-[13C6] glucose incorporation into purines or pyrimidines. In contrast, isotope tracing with [13C5, 15N2] glutamine showed increased utilization of glutamine for synthesis of nucleotides, glutathione, and tricarboxylic acid intermediates and increased incorporation of labeled glutamine into pyruvate and lactate. Using a glycolytic rate assay, we confirmed that anaerobic glycolysis is increased in PKCδ-depleted cells; this was accompanied by a reduction in oxidative phosphorylation, as assayed using a mitochondrial stress assay. Importantly, pretreatment of cells with specific inhibitors of the PPP or glutaminase prior to irradiation reversed radioprotection in PKCδ-depleted cells, indicating that these cells have acquired codependency on the PPP and glutamine for survival. Our studies demonstrate that metabolic reprogramming to increase utilization of glutamine and nucleotide synthesis contributes to radioprotection in the context of PKCδ inhibition.","PeriodicalId":22621,"journal":{"name":"The Journal of Biological Chemistry","volume":" ","pages":"105186"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10061486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Porcine IKKε is involved in the STING-induced type I IFN antiviral response of the cytosolic DNA signaling pathway. 猪IKKε参与STING诱导的胞质DNA信号通路的I型IFN抗病毒反应。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-01 DOI: 10.1016/j.jbc.2023.105213

Jia Luo, Qi Cao, Jiajia Zhang, Sen Jiang, Nengwen Xia, Shaohua Sun, Wanglong Zheng, Nanhua Chen, Francois Meurens, Jianzhong Zhu

{"title":"Porcine IKKε is involved in the STING-induced type I IFN antiviral response of the cytosolic DNA signaling pathway.","authors":"Jia Luo, Qi Cao, Jiajia Zhang, Sen Jiang, Nengwen Xia, Shaohua Sun, Wanglong Zheng, Nanhua Chen, Francois Meurens, Jianzhong Zhu","doi":"10.1016/j.jbc.2023.105213","DOIUrl":"10.1016/j.jbc.2023.105213","url":null,"abstract":"The cyclic GMP-AMP synthase and stimulator of interferon (IFN) genes (cGAS-STING) pathway serves as a crucial component of innate immune defense and exerts immense antiviral activity by inducing the expression of type I IFNs. Currently, STING-activated production of type I IFNs has been thought to be mediated only by TANK-binding kinase 1 (TBK1). Here, we identified that porcine IKKε (pIKKε) is also directly involved in STING-induced type I IFN expression and antiviral response by using IKKε-/- porcine macrophages. Similar to pTBK1, pIKKε interacts directly with pSTING on the C-terminal tail. Furthermore, the TBK1-binding motif of pSTING C-terminal tail is essential for its interaction with pIKKε, and within the TBK1-binding motif, the leucine (L) 373 is also critical for the interaction. On the other hand, both kinase domain and scaffold dimerization domain of pIKKε participate in the interactions with pSTING. Consistently, the reconstitution of pIKKε and its mutants in IKKε-/- porcine macrophages corroborated that IKKε and its kinase domain and scaffold dimerization domain are all involved in the STING signaling and antiviral function. Thus, our findings deepen the understanding of porcine cGAS-STING pathway, which lays a foundation for effective antiviral therapeutics against porcine viral diseases.","PeriodicalId":22621,"journal":{"name":"The Journal of Biological Chemistry","volume":" ","pages":"105213"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10202065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism. 基质蛋白酶-2主要通过非促细胞分裂机制调节肝铁调素表达的基础水平来调节铁稳态。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-09 DOI: 10.1016/j.jbc.2023.105238

Caroline A Enns, Tyler Weiskopf, Richard H Zhang, Jeffrey Wu, Shall Jue, Makiko Kawaguchi, Hiroaki Kataoka, An-Sheng Zhang

{"title":"Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism.","authors":"Caroline A Enns, Tyler Weiskopf, Richard H Zhang, Jeffrey Wu, Shall Jue, Makiko Kawaguchi, Hiroaki Kataoka, An-Sheng Zhang","doi":"10.1016/j.jbc.2023.105238","DOIUrl":"10.1016/j.jbc.2023.105238","url":null,"abstract":"Matriptase-2 (MT2), encoded by TMPRSS6, is a membrane-anchored serine protease. It plays a key role in iron homeostasis by suppressing the iron-regulatory hormone, hepcidin. Lack of functional MT2 results in an inappropriately high hepcidin and iron-refractory iron-deficiency anemia. Mt2 cleaves multiple components of the hepcidin-induction pathway in vitro. It is inhibited by the membrane-anchored serine protease inhibitor, Hai-2. Earlier in vivo studies show that Mt2 can suppress hepcidin expression independently of its proteolytic activity. In this study, our data indicate that hepatic Mt2 was a limiting factor in suppressing hepcidin. Studies in Tmprss6-/- mice revealed that increases in dietary iron to ∼0.5% were sufficient to overcome the high hepcidin barrier and to correct iron-deficiency anemia. Interestingly, the increased iron in Tmprss6-/- mice was able to further upregulate hepcidin expression to a similar magnitude as in wild-type mice. These results suggest that a lack of Mt2 does not impact the iron induction of hepcidin. Additional studies of wild-type Mt2 and the proteolytic-dead form, fMt2S762A, indicated that the function of Mt2 is to lower the basal levels of hepcidin expression in a manner that primarily relies on its nonproteolytic role. This idea is supported by the studies in mice with the hepatocyte-specific ablation of Hai-2, which showed a marginal impact on iron homeostasis and no significant effects on iron regulation of hepcidin. Together, these observations suggest that the function of Mt2 is to set the basal levels of hepcidin expression and that this process is primarily accomplished through a nonproteolytic mechanism.","PeriodicalId":22621,"journal":{"name":"The Journal of Biological Chemistry","volume":" ","pages":"105238"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10551898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10204906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synergistic computational and experimental studies of a phosphoglycosyl transferase membrane/ligand ensemble. 磷酸糖基转移酶膜/配体系综的协同计算和实验研究。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-08-25 DOI: 10.1016/j.jbc.2023.105194

Ayan Majumder, Nemanja Vuksanovic, Leah C Ray, Hannah M Bernstein, Karen N Allen, Barbara Imperiali, John E Straub

{"title":"Synergistic computational and experimental studies of a phosphoglycosyl transferase membrane/ligand ensemble.","authors":"Ayan Majumder, Nemanja Vuksanovic, Leah C Ray, Hannah M Bernstein, Karen N Allen, Barbara Imperiali, John E Straub","doi":"10.1016/j.jbc.2023.105194","DOIUrl":"10.1016/j.jbc.2023.105194","url":null,"abstract":"Complex glycans serve essential functions in all living systems. Many of these intricate and byzantine biomolecules are assembled employing biosynthetic pathways wherein the constituent enzymes are membrane-associated. A signature feature of the stepwise assembly processes is the essentiality of unusual linear long-chain polyprenol phosphate-linked substrates of specific isoprene unit geometry, such as undecaprenol phosphate (UndP) in bacteria. How these enzymes and substrates interact within a lipid bilayer needs further investigation. Here, we focus on a small enzyme, PglC from Campylobacter, structurally characterized for the first time in 2018 as a detergent-solubilized construct. PglC is a monotopic phosphoglycosyl transferase that embodies the functional core structure of the entire enzyme superfamily and catalyzes the first membrane-committed step in a glycoprotein assembly pathway. The size of the enzyme is significant as it enables high-level computation and relatively facile, for a membrane protein, experimental analysis. Our ensemble computational and experimental results provided a high-level view of the membrane-embedded PglC/UndP complex. The findings suggested that it is advantageous for the polyprenol phosphate to adopt a conformation in the same leaflet where the monotopic membrane protein resides as opposed to additionally disrupting the opposing leaflet of the bilayer. Further, the analysis showed that electrostatic steering acts as a major driving force contributing to the recognition and binding of both UndP and the soluble nucleotide sugar substrate. Iterative computational and experimental mutagenesis support a specific interaction of UndP with phosphoglycosyl transferase cationic residues and suggest a role for critical conformational transitions in substrate binding and specificity.","PeriodicalId":22621,"journal":{"name":"The Journal of Biological Chemistry","volume":" ","pages":"105194"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10131099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

APOLLO, a testis-specific Drosophila ortholog of importin-4, mediates the loading of protamine-like protein Mst77F into sperm chromatin. APOLLO是一种重要蛋白-4的睾丸特异性果蝇直系同源物，介导精蛋白样蛋白Mst77F进入精子染色质。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-02 DOI: 10.1016/j.jbc.2023.105212

Alexander V Emelyanov, Daniel Barcenilla-Merino, Benjamin Loppin, Dmitry V Fyodorov

{"title":"APOLLO, a testis-specific Drosophila ortholog of importin-4, mediates the loading of protamine-like protein Mst77F into sperm chromatin.","authors":"Alexander V Emelyanov, Daniel Barcenilla-Merino, Benjamin Loppin, Dmitry V Fyodorov","doi":"10.1016/j.jbc.2023.105212","DOIUrl":"10.1016/j.jbc.2023.105212","url":null,"abstract":"DNA in sperm is packed with small, charged proteins termed SNBPs (sperm nuclear basic proteins), including mammalian and Drosophila protamines. During spermiogenesis, somatic-type chromatin is taken apart and replaced with sperm chromatin in a multistep process leading to an extraordinary condensation of the genome. During fertilization, the ova face a similarly challenging task of SNBP eviction and reassembly of nucleosome-based chromatin. Despite its importance for the animal life cycle, sperm chromatin metabolism, including the biochemical machinery mediating the mutual replacement of histones and SNBPs, remains poorly studied. In Drosophila, Mst77F is one of the first SNBPs loaded into the spermatid nuclei. It persists in mature spermatozoa and is essential for sperm compaction and male fertility. Here, by using in vitro biochemical assays, we identify chaperones that can mediate the eviction and loading of Mst77F on DNA, thus facilitating the interconversions of chromatin forms in the male gamete. Unlike NAP1 and TAP/p32 chaperones that disassemble Mst77F-DNA complexes, ARTEMIS and APOLLO, orthologs of mammalian importin-4 (IPO4), mediate the deposition of Mst77F on DNA or oligonucleosome templates, accompanied by the dissociation of histone-DNA complexes. In vivo, a mutation of testis-specific Apollo brings about a defect of Mst77F loading, abnormal sperm morphology, and male infertility. We identify IPO4 ortholog APOLLO as a critical component of sperm chromatin assembly apparatus in Drosophila. We discover that in addition to recognized roles in protein traffic, a nuclear transport receptor (IPO4) can function directly in chromatin remodeling as a dual, histone- and SNBP-specific, chaperone.","PeriodicalId":22621,"journal":{"name":"The Journal of Biological Chemistry","volume":" ","pages":"105212"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10518910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Differential regulation of tetramerization of the AMPA receptor glutamate-gated ion channel by auxiliary subunits. 辅助亚基对AMPA受体谷氨酸门控离子通道四聚作用的差异调节。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-09 DOI: 10.1016/j.jbc.2023.105227

Noele Certain, Quan Gan, Joseph Bennett, Helen Hsieh, Lonnie P Wollmuth

{"title":"Differential regulation of tetramerization of the AMPA receptor glutamate-gated ion channel by auxiliary subunits.","authors":"Noele Certain, Quan Gan, Joseph Bennett, Helen Hsieh, Lonnie P Wollmuth","doi":"10.1016/j.jbc.2023.105227","DOIUrl":"10.1016/j.jbc.2023.105227","url":null,"abstract":"α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) auxiliary subunits are specialized, nontransient binding partners of AMPARs that modulate AMPAR channel gating properties and pharmacology, as well as their biogenesis and trafficking. The most well-characterized families of auxiliary subunits are transmembrane AMPAR regulatory proteins (TARPs), cornichon homologs (CNIHs), and the more recently discovered GSG1-L. These auxiliary subunits can promote or reduce surface expression of AMPARs (composed of GluA1-4 subunits) in neurons, thereby impacting their functional role in membrane signaling. Here, we show that CNIH-2 enhances the tetramerization of WT and mutant AMPARs, presumably by increasing the overall stability of the tetrameric complex, an effect that is mainly mediated by interactions with the transmembrane domain of the receptor. We also find CNIH-2 and CNIH-3 show receptor subunit-specific actions in this regard with CNIH-2 enhancing both GluA1 and GluA2 tetramerization, whereas CNIH-3 only weakly enhances GluA1 tetramerization. These results are consistent with the proposed role of CNIHs as endoplasmic reticulum cargo transporters for AMPARs. In contrast, TARP γ-2, TARP γ-8, and GSG1-L have no or negligible effect on AMPAR tetramerization. On the other hand, TARP γ-2 can enhance receptor tetramerization but only when directly fused with the receptor at a maximal stoichiometry. Notably, surface expression of functional AMPARs was enhanced by CNIH-2 to a greater extent than TARP γ-2, suggesting that this distinction aids in maturation and membrane expression. These experiments define a functional distinction between CNIHs and other auxiliary subunits in the regulation of AMPAR biogenesis.","PeriodicalId":22621,"journal":{"name":"The Journal of Biological Chemistry","volume":" ","pages":"105227"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10167470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preservation of circadian rhythm in hepatocellular cancer. 肝细胞癌症昼夜节律的保护。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-14 DOI: 10.1016/j.jbc.2023.105251

Yanyan Yang, Ashraf N Abdo, Hiroaki Kawara, Christopher P Selby, Aziz Sancar

{"title":"Preservation of circadian rhythm in hepatocellular cancer.","authors":"Yanyan Yang, Ashraf N Abdo, Hiroaki Kawara, Christopher P Selby, Aziz Sancar","doi":"10.1016/j.jbc.2023.105251","DOIUrl":"10.1016/j.jbc.2023.105251","url":null,"abstract":"Circadian rhythms are controlled at the cellular level by a molecular clock consisting of several genes/proteins engaged in a transcription-translation-degradation feedback loop. These core clock proteins regulate thousands of tissue-specific genes. Regarding circadian control in neoplastic tissues, reports to date have demonstrated anomalous circadian function in tumor models and cultured tumor cells. We have extended these studies by analyzing circadian rhythmicity genome-wide in a mouse model of liver cancer, in which mice treated with diethylnitrosamine at 15 days develop liver tumors by 6 months. We injected tumor-bearing and control tumor-free mice with cisplatin every 2 h over a 24-h cycle; 2 h after each injection mice were sacrificed and gene expression was measured by XR-Seq (excision repair sequencing) assay. Rhythmic expression of several core clock genes was observed in both healthy liver and tumor, with clock genes in tumor exhibiting typically robust amplitudes and a modest phase advance. Interestingly, although normal hepatic cells and hepatoma cancer cells expressed a comparable number of genes with circadian rhythmicity (clock-controlled genes), there was only about 10% overlap between the rhythmic genes in normal and cancerous cells. \"Rhythmic in tumor only\" genes exhibited peak expression times mainly in daytime hours, in contrast to the more common pre-dawn and pre-dusk expression times seen in healthy livers. Differential expression of genes in tumors and healthy livers across time may present an opportunity for more efficient anticancer drug treatment as a function of treatment time.","PeriodicalId":22621,"journal":{"name":"The Journal of Biological Chemistry","volume":" ","pages":"105251"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10610441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel phosphorylation site involved in dissociating RAF kinase from the scaffolding protein 14-3-3 and disrupting RAF dimerization. 一种新的磷酸化位点，参与从支架蛋白14-3-3中解离RAF激酶并破坏RAF二聚化。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-08-23 DOI: 10.1016/j.jbc.2023.105188

Alison Yu, Duc Nguyen, Thomas Joseph Nguyen, Zhihong Wang

{"title":"A novel phosphorylation site involved in dissociating RAF kinase from the scaffolding protein 14-3-3 and disrupting RAF dimerization.","authors":"Alison Yu, Duc Nguyen, Thomas Joseph Nguyen, Zhihong Wang","doi":"10.1016/j.jbc.2023.105188","DOIUrl":"10.1016/j.jbc.2023.105188","url":null,"abstract":"Rapidly accelerated fibrosarcoma (ARAF, BRAF, CRAF) kinase is central to the MAPK pathway (RAS-RAF-MEK-ERK). Inactive RAF kinase is believed to be monomeric, autoinhibited, and cytosolic, while activated RAF is recruited to the membrane via RAS-GTP, leading to the relief of autoinhibition, phosphorylation of key regulatory sites, and dimerization of RAF protomers. Although it is well known that active and inactive BRAF have differential phosphorylation sites that play a crucial role in regulating BRAF, key details are still missing. In this study, we report the characterization of a novel phosphorylation site, BRAFS732 (equivalent in CRAFS624), located in proximity to the C-terminus binding motif for the 14-3-3 scaffolding protein. At the C terminus, 14-3-3 binds to BRAFpS729 (CRAFpS621) and enhances RAF dimerization. We conducted mutational analysis of BRAFS732A/E and CRAFS624A/E and revealed that the phosphomimetic S→E mutant decreases 14-3-3 association and RAF dimerization. In normal cell signaling, dimerized RAF phosphorylates MEK1/2, which is observed in the phospho-deficient S→A mutant. Our results suggest that phosphorylation and dephosphorylation of this site fine-tune the association of 14-3-3 and RAF dimerization, ultimately impacting MEK phosphorylation. We further characterized the BRAF homodimer and BRAF:CRAF heterodimer and identified a correlation between phosphorylation of this site with drug sensitivity. Our work reveals a novel negative regulatory role for phosphorylation of BRAFS732 and CRAFS624 in decreasing 14-3-3 association, dimerization, and MEK phosphorylation. These findings provide insight into the regulation of the MAPK pathway and may have implications for cancers driven by mutations in the pathway.","PeriodicalId":22621,"journal":{"name":"The Journal of Biological Chemistry","volume":" ","pages":"105188"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10062975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reply to Record et al. "The role of PMP22 T118M in Charcot-Marie-Tooth disease remains unsolved". 回复记录等。“PMP22 T118M在Charcot-Marie Tooth病中的作用尚未解决”。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-14 DOI: 10.1016/j.jbc.2023.105181

Katherine M Stefanski, Geoffrey C Li, Justin T Marinko, Bruce D Carter, David C Samuels, Charles R Sanders

引用次数: 0

SUMOylation of Smad2 mediates TGF-β-regulated endothelial-mesenchymal transition. Smad2的SUMO化介导TGF-β调节的内皮-间充质转化。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-09 DOI: 10.1016/j.jbc.2023.105244

Qi Su, Xu Chen, Xing Ling, Danqing Li, Xiang Ren, Yang Zhao, Yanyan Yang, Yuhang Liu, Anqi He, Xinjie Zhu, Xinyi Yang, Wenbin Lu, Hongmei Wu, Yitao Qi

{"title":"SUMOylation of Smad2 mediates TGF-β-regulated endothelial-mesenchymal transition.","authors":"Qi Su, Xu Chen, Xing Ling, Danqing Li, Xiang Ren, Yang Zhao, Yanyan Yang, Yuhang Liu, Anqi He, Xinjie Zhu, Xinyi Yang, Wenbin Lu, Hongmei Wu, Yitao Qi","doi":"10.1016/j.jbc.2023.105244","DOIUrl":"10.1016/j.jbc.2023.105244","url":null,"abstract":"Endothelial-mesenchymal transition (EndoMT) is a complex biological process in which endothelial cells are transformed into mesenchymal cells, and dysregulated EndoMT causes a variety of pathological processes. Transforming growth factor beta (TGF-β) signaling effectively induces the EndoMT process in endothelial cells, and Smad2 is the critical protein of the TGF-β signaling pathway. However, whether small ubiquitin-like modifier modification (SUMOylation) is involved in EndoMT remains unclear. Here, we show that Smad2 is predominantly modified by SUMO1 at two major SUMOylation sites with PIAS2α as the primary E3 ligase, whereas SENP1 (sentrin/SUMO-specific protease 1) mediates the deSUMOylation of Smad2. In addition, we identified that SUMOylation significantly enhances the transcriptional activity and protein stability of Smad2, regulating the expression of downstream target genes. SUMOylation increases the phosphorylation of Smad2 and the formation of the Smad2-Smad4 complex, thus promoting the nuclear translocation of Smad2. Ultimately, the wildtype, but not SUMOylation site mutant Smad2 facilitated the EndoMT process. More importantly, TGF-β enhances the nuclear translocation of Smad2 by enhancing its SUMOylation and promoting the EndoMT process. These results demonstrate that SUMOylation of Smad2 plays a critical role in the TGF-β-mediated EndoMT process, providing a new theoretical basis for the treatment and potential drug targets of EndoMT-related clinical diseases.","PeriodicalId":22621,"journal":{"name":"The Journal of Biological Chemistry","volume":" ","pages":"105244"},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10570702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10202583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0