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Influence of native thin filament type on the regulation of atrial and ventricular myosin motor activity. 原生细丝类型对心房和心室肌球蛋白运动活性调节的影响
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2024-10-05 DOI: 10.1016/j.jbc.2024.107854
Emrulla Spahiu, Petra Uta, Theresia Kraft, Arnab Nayak, Mamta Amrute-Nayak
{"title":"Influence of native thin filament type on the regulation of atrial and ventricular myosin motor activity.","authors":"Emrulla Spahiu, Petra Uta, Theresia Kraft, Arnab Nayak, Mamta Amrute-Nayak","doi":"10.1016/j.jbc.2024.107854","DOIUrl":"10.1016/j.jbc.2024.107854","url":null,"abstract":"<p><p>Ca<sup>2+</sup>-mediated activation of thin filaments is a crucial step in initiating striated muscle contraction. To gain mechanistic insight into this regulatory process, thin filament (TF) components and myosin motors from diverse species and tissue sources are often combined in minimal in vitro systems. The contribution of tissue-specific TF composition with native myosin motors in generating contraction speed remains unclear. To examine TF-mediated regulation, we established a procedure to purify native TFs (nTF) and myosin motors (M-II) from the same cardiac tissue samples as low as 10 mg and investigated their influence on gliding speeds and Ca<sup>2+</sup> sensitivity. The rabbit atrial and ventricular nTFs and M-II were assessed in in vitro nTF motility experiments under varying Ca<sup>2+</sup> concentrations. The speed-pCa relationship yielded a maximum TF speed of 2.58 μm/s for atrial (aM-II) and 1.51 μm/s for ventricular myosin (vM-II), both higher than the respective unregulated actin filament gliding speeds. The Ca<sup>2+</sup> sensitivity was different for both protein sources. After swapping the nTFs, the ventricular TFs increased their gliding speed on atrial myosin, while the atrial nTFs reduced their gliding speed on ventricular myosin. Swapping of the nTFs decreased the calcium sensitivity for both vM-II and aM-II, indicating a strong influence of the thin filament source. These studies suggest that the nTF-myosin combination is critical to understanding the Ca<sup>2+</sup> sensitivity of the shortening speed. Our approach is highly relevant to studying precious human cardiac samples, that is, small myectomy samples, to address the alteration of contraction speed and Ca<sup>2+</sup> sensitivity in cardiomyopathies.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380923","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
Upregulation of nuclear protein Hemgn by transcriptional repressor Gfi1 through repressing PU.1 contributes to the anti-apoptotic activity of Gfi1. 转录抑制因子 Gfi1 通过抑制 PU.1 上调核蛋白 Hemgn,有助于 Gfi1 的抗凋亡活性。
IF 4.8 2区 生物学
Journal of Biological Chemistry Pub Date : 2024-10-05 DOI: 10.1016/j.jbc.2024.107860
Binod G C,Laney Jia Hoyt,Sinisa Dovat,Fan Dong
{"title":"Upregulation of nuclear protein Hemgn by transcriptional repressor Gfi1 through repressing PU.1 contributes to the anti-apoptotic activity of Gfi1.","authors":"Binod G C,Laney Jia Hoyt,Sinisa Dovat,Fan Dong","doi":"10.1016/j.jbc.2024.107860","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107860","url":null,"abstract":"Gfi1 is a transcriptional repressor that plays a critical role in hematopoiesis. The repressive activity of Gfi1 is mediated mainly by its SNAG domain that interacts with and thereby recruits the histone demethylase LSD1 to its target genes. An important function of Gfi1 is to protect hematopoietic cells against stress-induced apoptosis, which has been attributed to its participation in the posttranscriptional modifications of p53 protein, leading to suppression of p53 activity. In this study, we show that Gfi1 upregulated the expression of Hemgn, a nuclear protein, through a 16-bp promoter region spanning from +47 to +63 bp relative to the transcription start site (TSS), which was dependent on its interaction with LSD1. We further demonstrate that Gfi1, Ikaros and PU.1 bound to this 16-bp region. However, while Ikaros activated Hemgn and collaborated with Gfi1 to augment Hemgn expression, it was not required for Gfi1-mediated Hemgn upregulation. In contrast, PU.1 repressed Hemgn and inhibited Hemgn upregulation by Gfi1. Notably, PU.1 knockdown and deficiency, while augmenting Hemgn expression, abolished Hemgn upregulation by Gfi1. PU.1 (Spi-1) has been shown to be repressed by Gfi1. We show here that PU.1 repression by Gfi1 preceded and correlated well with Hemgn upregulation. Thus, our date strongly suggest that Gfi1 upregulates Hemgn by repressing PU.1. In addition, we demonstrate that Hemgn upregulation contributed to the anti-apoptotic activity of Gfi1 in a p53-independent manner.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385412","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
Experimental variables determine the outcome of RAS-RAS interactions. 实验变量决定了 RAS-RAS 相互作用的结果。
IF 4.8 2区 生物学
Journal of Biological Chemistry Pub Date : 2024-10-05 DOI: 10.1016/j.jbc.2024.107859
Zhiwei Zhou,Tra Ly Nguyen,Xingxiao Li,Christel Poujol,Ewa Berlinska,Sandra Vietti Michelina,Jonas N Kapp,Andreas Plückthun,Monte M Winslow,Chiara Ambrogio,Yibing Shan,David Santamaría,Kenneth D Westover
{"title":"Experimental variables determine the outcome of RAS-RAS interactions.","authors":"Zhiwei Zhou,Tra Ly Nguyen,Xingxiao Li,Christel Poujol,Ewa Berlinska,Sandra Vietti Michelina,Jonas N Kapp,Andreas Plückthun,Monte M Winslow,Chiara Ambrogio,Yibing Shan,David Santamaría,Kenneth D Westover","doi":"10.1016/j.jbc.2024.107859","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107859","url":null,"abstract":"RAS clustering at the cell membrane is critical to activate signaling in cells, but whether this clustering is mediated exclusively by its c-terminal hypervariable region, receives contributions from the G-domain of RAS, and/or is influenced by secondary effectors has been intensely debated. Reports that G-domain mutations do not modulate RAS-RAS interactions, have led some to question the validity of previous experiments that indicate the G-domain plays a role in RAS clustering/interactions. Here we reconcile these findings by clarifying the impact of experimental variables, such as protein expression levels, cellular context, RAS zygosity, and secondary effector interactions on RAS clustering. Lack of control over these variables impact the results using G-domain mutations across various assay systems and can lead to unsound conclusions.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385470","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
A putative cAMP-binding protein in Trypanosoma brucei cooperates with FLAM3 to promote flagellar connection and cell morphogenesis. 布氏锥虫中一种推定的 cAMP 结合蛋白与 FLAM3 合作促进鞭毛连接和细胞形态发生。
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2024-10-05 DOI: 10.1016/j.jbc.2024.107856
Qing Zhou, Phu Van Nguyen, Ziyin Li
{"title":"A putative cAMP-binding protein in Trypanosoma brucei cooperates with FLAM3 to promote flagellar connection and cell morphogenesis.","authors":"Qing Zhou, Phu Van Nguyen, Ziyin Li","doi":"10.1016/j.jbc.2024.107856","DOIUrl":"10.1016/j.jbc.2024.107856","url":null,"abstract":"<p><p>Trypanosoma brucei is a flagellated parasitic protozoan, and within the insect vector the parasite transitions from the trypomastigote form to the epimastigote form by repositioning its mitochondrial genome and relocating the flagellum. The mechanisms underlying such morphology changes are still poorly understood, but several flagellum-localized proteins are involved in this process by modulating the flagellum attachment zone (FAZ) that adheres the flagellum to the cell membrane. We report here a putative cAMP-binding protein named cAMP-BP1, which promotes flagellar connection and morphology transition. cAMP-BP1 contains two cyclic nucleotide-binding domains and five calcium-binding C2 domains and localizes to the flagella connector and the new FAZ tip. Depletion of cAMP-BP1 in the trypomastigote form of T. brucei causes major morphology changes, generating epimastigote-like cells with repositioned kinetoplast and relocated flagellum. At the flagella connector and the new FAZ tip, cAMP-BP1 associates with FLAM3, a regulator of morphology transition, depends on the latter for localization, and is required for FLAM3 localization to the flagella connector. Knockdown of cAMP-BP1 inhibits FAZ elongation and disrupts flagellar connection by impairing flagella connector structural integrity. These results identify a flagella connector- and new FAZ tip-localized protein as a regulator of morphology transition and flagellar connection in trypanosomes and uncover its functional interplay with FLAM3 to promote FAZ elongation for maintaining trypomastigote morphology.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380921","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
Cofactor Binding Triggers Rapid Conformational Remodelling of the Active Site of a Methyltransferase Ribozyme. 辅因子结合引发甲基转移酶波形酶活性位点的快速构象重塑
IF 4.8 2区 生物学
Journal of Biological Chemistry Pub Date : 2024-10-05 DOI: 10.1016/j.jbc.2024.107863
Hengyi Jiang,Getong Liu,Yanqing Gao,Jianhua Gan,Dongrong Chen,Alastair I H Murchie
{"title":"Cofactor Binding Triggers Rapid Conformational Remodelling of the Active Site of a Methyltransferase Ribozyme.","authors":"Hengyi Jiang,Getong Liu,Yanqing Gao,Jianhua Gan,Dongrong Chen,Alastair I H Murchie","doi":"10.1016/j.jbc.2024.107863","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107863","url":null,"abstract":"The methyltransferase ribozyme SMRZ-1 utilizes S-adenosyl-methionine (SAM) and Cu (II) ions to methylate RNA. Comparison of the SAM bound and unbound RNA structures has shown a conformational change in the RNA. However, the contribution of specific interactions and the role of a pseudo-triplex motif in the catalytic centre on the methylation reaction is not completely understood. In this study, we have used atomic substitutions and mutational analysis to investigate the reaction specificity and the key interactions required for catalysis. Substitution of the fluorescent nucleotide 2-aminopurine within the active ribozyme enabled the conformational dynamics of the RNA upon co-factor binding to be explored using fluorescence spectroscopy. We show that fast co-factor binding (t1/2 ∼ 0.7 seconds) drives a conformational change in the RNA to facilitate methyl group transfer. The importance of stacking interactions at the pseudo-triplex motif and chelation of the Cu (II) ion were shown to be essential for SAM binding.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385411","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
Temperature-controlled molecular switches in mammalian cells. 哺乳动物细胞中的温控分子开关
IF 4.8 2区 生物学
Journal of Biological Chemistry Pub Date : 2024-10-05 DOI: 10.1016/j.jbc.2024.107865
Eva Absmeier,Florian Heyd
{"title":"Temperature-controlled molecular switches in mammalian cells.","authors":"Eva Absmeier,Florian Heyd","doi":"10.1016/j.jbc.2024.107865","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107865","url":null,"abstract":"Temperature is an omnipresent factor impacting on many aspects of life. In bacteria and ectothermic eukaryotes various thermosensors and temperature-controlled switches have been described, ranging from RNA thermometers controlling the heat shock response in prokaryotes to temperature-dependent sex determination in reptiles, likely controlled through protein phosphorylation. However, the impact of subtle changes of human core body temperature are only beginning to be acknowledged. In this review, we will discuss thermosensing mechanisms and their functional implications with a focus on mammalian cells, also in the context of disease conditions. We will point out open questions and possible future directions for this emerging research field, which, in addition to molecular-mechanistic insights, holds the potential for the development of new therapeutic approaches.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385415","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
Activity and phosphatidylcholine transfer protein interactions of skeletal muscle thioesterase Them2 enable hepatic steatosis and insulin resistance. 骨骼肌硫酯酶 Them2 的活性和磷脂酰胆碱转移蛋白的相互作用可导致肝脏脂肪变性和胰岛素抵抗。
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2024-10-05 DOI: 10.1016/j.jbc.2024.107855
Yang Xie, Xu Liu, Wenpeng Liu, Logan R Carr, Luke P Lee, Norihiro Imai, Eric A Ortlund, David E Cohen
{"title":"Activity and phosphatidylcholine transfer protein interactions of skeletal muscle thioesterase Them2 enable hepatic steatosis and insulin resistance.","authors":"Yang Xie, Xu Liu, Wenpeng Liu, Logan R Carr, Luke P Lee, Norihiro Imai, Eric A Ortlund, David E Cohen","doi":"10.1016/j.jbc.2024.107855","DOIUrl":"10.1016/j.jbc.2024.107855","url":null,"abstract":"<p><p>Thioesterase superfamily member 2 (Them2), a long-chain fatty acyl-CoA thioesterase that is highly expressed in oxidative tissues, interacts with phosphatidylcholine transfer protein (PC-TP) to regulate hepatic lipid and glucose metabolism and to suppress insulin signaling. High-fat diet-fed mice lacking Them2 globally or specifically in skeletal muscle, but not liver, exhibit reduced hepatic steatosis and insulin resistance. Here, we report that the capacity of Them2 in skeletal muscle to promote hepatic steatosis and insulin resistance depends on both its catalytic activity and interaction with PC-TP. Two residues of Them2 catalytic site were mutated (N50A/D65A) to produce the inactive enzyme while maintaining its homotetrameric structure and interaction with PC-TP. Restoration of skeletal muscle expression in Them2<sup>-/-</sup> mice using recombinant adeno-associated virus revealed that WT, but not N50A/D65A Them2, promoted high-fat diet-induced weight gain and hepatic steatosis. This was accompanied by greater impairment of insulin sensitivity in WT than N50A/D65A Them2. Pharmacological inhibition or genetic ablation of PC-TP attenuated these effects. In reductionist experiments, conditioned medium collected from WT primary cultured myotubes promoted excess lipid accumulation in oleic acid-treated primary cultured hepatocytes relative to Them2<sup>-/-</sup> myotubes, which was attributable to secreted extracellular vesicles. Reconstitution of Them2 expression in Them2<sup>-/-</sup> myotubes affirmed the requirements for catalytic activity and PC-TP interactions for extracellular vesicles to promote lipid accumulation in hepatocytes. These studies provide valuable mechanistic insights, whereby Them2 in skeletal muscle promotes hepatic steatosis and establish both Them2 and PC-TP as attractive targets for managing metabolic dysfunction-associated steatotic liver disease.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380922","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
Methylation and phosphorylation of formin homology domain proteins (Fhod1 and Fhod3) by protein arginine methyltransferase 7 (PRMT7) and Rho Kinase (ROCK1). 蛋白精氨酸甲基转移酶 7 (PRMT7) 和 Rho 激酶 (ROCK1) 对甲形蛋白同源结构域蛋白(Fhod1 和 Fhod3)的甲基化和磷酸化。
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2024-10-03 DOI: 10.1016/j.jbc.2024.107857
Troy L Lowe, Dylan A Valencia, Vicente E Velasquez, Margot E Quinlan, Steven G Clarke
{"title":"Methylation and phosphorylation of formin homology domain proteins (Fhod1 and Fhod3) by protein arginine methyltransferase 7 (PRMT7) and Rho Kinase (ROCK1).","authors":"Troy L Lowe, Dylan A Valencia, Vicente E Velasquez, Margot E Quinlan, Steven G Clarke","doi":"10.1016/j.jbc.2024.107857","DOIUrl":"10.1016/j.jbc.2024.107857","url":null,"abstract":"<p><p>Protein post translational modifications (PTMs) can regulate biological processes by altering an amino acid's bulkiness, charge, and hydrogen bonding interactions. Common modifications include phosphorylation, methylation, acetylation and ubiquitylation. Although a primary focus of studying PTMs is understanding the effects of a single amino acid modification, the possibility of additional modifications increases the complexity. For example, substrate recognition motifs for arginine methyltransferases and some serine/threonine kinases overlap, leading to potential enzymatic crosstalk. In this study we have shown that the human family of formin homology domain containing proteins (Fhods) contain a substrate recognition motif specific for human protein arginine methyltransferase 7 (PRMT7). In particular, PRMT7 methylates two arginine residues in the diaphanous autoinhibitory domain (DAD) of the family of Fhod proteins: R1588 and/or R1590 of Fhod3 isoform 4. Additionally, we confirmed that S1589 and S1595 in the DAD domain of Fhod3 can be phosphorylated by Rho/ROCK1 kinase. Significantly, we have determined that if S1589 is phosphorylated then PRMT7 cannot subsequently methylate R1588 or R1590. In contrast, if R1588 or R1590 of Fhod3 is methylated then ROCK1 phosphorylation activity is only slightly affected. Finally, we show that the interaction of the N-terminal DID domain can also inhibit the methylation of the DAD domain. Taken together these results suggest that the family of Fhod proteins, potential in vivo substrates for PRMT7, might be regulated by a combination of methylation and phosphorylation.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377942","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
Comprehensive identification, isolation, and culture of human breast cell types. 全面鉴定、分离和培养人类乳腺细胞类型。
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2024-10-01 Epub Date: 2024-08-07 DOI: 10.1016/j.jbc.2024.107637
Kate Thi, Katelyn Del Toro, Yamhilette Licon-Munoz, Rosalyn W Sayaman, William C Hines
{"title":"Comprehensive identification, isolation, and culture of human breast cell types.","authors":"Kate Thi, Katelyn Del Toro, Yamhilette Licon-Munoz, Rosalyn W Sayaman, William C Hines","doi":"10.1016/j.jbc.2024.107637","DOIUrl":"10.1016/j.jbc.2024.107637","url":null,"abstract":"<p><p>Tissues are formed and shaped by cells of many different types and are orchestrated through countless interactions. Deciphering a tissue's biological complexity thus requires studying it at cell-level resolution, where molecular and biochemical features of different cell types can be explored and thoroughly dissected. Unfortunately, the lack of comprehensive methods to identify, isolate, and culture each cell type from many tissues has impeded progress. Here, we present a method for the breadth of cell types composing the human breast. Our goal has long been to understand the essence of each of these different breast cell types, to reveal the underlying biology explaining their intrinsic features, the consequences of interactions, and their contributions to the tissue. This biological exploration has required cell purification, deep-RNA sequencing, and a thorough dissection of the genes and pathways defining each cell type. While the molecular analysis is presented in an adjoining article, we present here an exhaustive cellular dissection of the human breast and explore its cellular composition and histological organization. Moreover, we introduce a novel FACS antibody panel and rigorous gating strategy capable of isolating each of the 12 major breast cell types to purity. Finally, we describe the creation of primary cell models from nearly every breast cell type-some the first of their kind-and submit these as critical tools for studying the dynamic cellular interactions within breast tissues and tumors. Together, this body of work delivers a unique perspective of the breast, revealing insights into its cellular, molecular, and biochemical composition.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11459906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Novel mechanism of cyclic nucleotide crosstalk mediated by PKG-dependent proteasomal degradation of the Hsp90 client protein phosphodiesterase 3A. 由 PKG 依赖蛋白酶体降解 Hsp90 客户蛋白磷酸二酯酶 3A 介导的环状核苷酸串联的新机制
IF 4 2区 生物学
Journal of Biological Chemistry Pub Date : 2024-10-01 Epub Date: 2024-08-28 DOI: 10.1016/j.jbc.2024.107723
Evgeny A Zemskov, Marina A Zemskova, Xiaomin Wu, Santiago Moreno Caceres, David Caraballo Delgado, Manivannan Yegambaram, Qing Lu, Panfeng Fu, Ting Wang, Stephen M Black
{"title":"Novel mechanism of cyclic nucleotide crosstalk mediated by PKG-dependent proteasomal degradation of the Hsp90 client protein phosphodiesterase 3A.","authors":"Evgeny A Zemskov, Marina A Zemskova, Xiaomin Wu, Santiago Moreno Caceres, David Caraballo Delgado, Manivannan Yegambaram, Qing Lu, Panfeng Fu, Ting Wang, Stephen M Black","doi":"10.1016/j.jbc.2024.107723","DOIUrl":"10.1016/j.jbc.2024.107723","url":null,"abstract":"<p><p>Endothelial cAMP-specific phosphodiesterase PDE3A is one of the major negative regulators of the endothelial barrier function in acute lung injury models. However, the mechanisms underlying its regulation still need to be fully resolved. We show here that the PDE3A is a newly described client of the molecular chaperone heat shock protein 90 (hsp90). In endothelial cells (ECs), hsp90 inhibition by geldanamycin (GA) led to a disruption of the hsp90/PDE3A complex, followed by a significant decrease in PDE3A protein levels. The decrease in PDE3A protein levels was ubiquitin-proteasome-dependent and required the activity of the E3 ubiquitin ligase C terminus of Hsc70-interacting protein. GA treatment also enhanced the association of PDE3A with hsp70, which partially prevented PDE3A degradation. GA-induced decreases in PDE3A protein levels correlated with decreased PDE3 activity and increased cAMP levels in EC. We also demonstrated that protein kinase G-dependent phosphorylation of PDE3A at Ser<sup>654</sup> can signal the dissociation of PDE3A from hsp90 and PDE3A degradation. This was confirmed by endogenous PDE3A phosphorylation and degradation in 8-Br-cGMP- or 8-CPT-cGMP- and Bay 41-8543-stimulated EC and comparisons of WT- and phospho-mimic S<sup>654</sup>D mutant PDE3A protein stability in transiently transfected HEK293 cells. In conclusion, we have identified a new mechanism of PDE3A regulation mediated by the ubiquitin-proteasome system. Further, the degradation of PDE3A is controlled by the phosphorylation of S<sup>654</sup> and the interaction with hsp90. We speculate that targeting the PDE3A/hsp90 complex could be a therapeutic approach for acute lung injury.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11497409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
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