Journal of Biological Chemistry最新文献_第10页

DNA damage-induced p53 downregulates expression of RAG1 through a negative feedback loop involving miR-34a and FOXP1. DNA 损伤诱导的 p53 通过涉及 miR-34a 和 FOXP1 的负反馈回路下调 RAG1 的表达。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-23 DOI: 10.1016/j.jbc.2024.107922

Katarina Ochodnicka-Mackovicova, Martine van Keimpema, Marcel Spaargaren, Carel J M van Noesel, Jeroen E J Guikema

{"title":"DNA damage-induced p53 downregulates expression of RAG1 through a negative feedback loop involving miR-34a and FOXP1.","authors":"Katarina Ochodnicka-Mackovicova, Martine van Keimpema, Marcel Spaargaren, Carel J M van Noesel, Jeroen E J Guikema","doi":"10.1016/j.jbc.2024.107922","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107922","url":null,"abstract":"During the maturation of pre-B cells, the recombination activating gene 1 and 2 (RAG1/2) endonuclease complex plays a crucial role in coordinating V(D)J recombination by introducing DNA breaks in immunoglobulin (Ig) loci. Dysregulation of RAG1/2 has been linked to the onset of B-cell malignancies, yet the mechanisms controlling RAG1/2 in pre-B cells exposed to excessive DNA damage are not fully understood. In this study, we show that DNA damage-induced activation of p53 initiates a negative-feedback loop which rapidly downregulates RAG1 levels. This feedback loop involves ataxia telangiectasia mutated (ATM) activation, subsequent stabilization of p53, and modulation of microRNA-34a (miR-34a) levels, which is one of the p53 targets. Notably, this loop incorporates transcription factor forkhead box P1 (FOXP1) as a downstream effector. The absence of p53 resulted in an increased proportion of IgM+ cells prompted to upregulate RAG1/2 and to undergo Ig light chain (Igl) recombination. Similar results were obtained in primary pre-B cells with depleted levels of miR-34a. We propose that in pre-B cells undergoing Ig gene recombination, the DNA breaks activate a p53/miR-34a/FOXP1-mediated negative-feedback loop that contributes to the rapid downregulation of RAG. This regulation limits the RAG-dependent DNA damage, thereby protecting the stability of the genome during V(D)J rearrangement in developing B cells.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"107922"},"PeriodicalIF":4.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500921","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

DNA polymerase ζ has robust reverse transcriptase activity relative to other cellular DNA polymerases. 与其他细胞 DNA 聚合酶相比，DNA 聚合酶 ζ 具有强大的逆转录酶活性。

IF 5.4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-23 DOI: 10.1016/j.jbc.2024.107918

Ryan Mayle, William K Holloman, Michael E O'Donnell

{"title":"DNA polymerase ζ has robust reverse transcriptase activity relative to other cellular DNA polymerases.","authors":"Ryan Mayle, William K Holloman, Michael E O'Donnell","doi":"10.1016/j.jbc.2024.107918","DOIUrl":"10.1016/j.jbc.2024.107918","url":null,"abstract":"Cell biology and genetic studies have demonstrated that DNA double-strand break (DSB) repair can be performed using an RNA transcript that spans the site of the DNA break as a template for repair. This type of DSB repair requires a reverse transcriptase to convert an RNA sequence into DNA to facilitate repair of the break, rather than copying from a DNA template as in canonical DSB repair. Translesion synthesis (TLS) DNA polymerases (Pol) are often more promiscuous than DNA Pols, raising the notion that reverse transcription could be performed by a TLS Pol. Indeed, several studies have demonstrated that human Pol η has reverse transcriptase activity, while others have suggested that the yeast TLS Pol ζ is involved. Here, we purify all seven known nuclear DNA Pols of Saccharomyces cerevisiae and compare their reverse transcriptase activities. The comparison shows that Pol ζ far surpasses Pol η and all other DNA Pols in reverse transcriptase activity. We find that Pol ζ reverse transcriptase activity is not affected by RPA or RFC/PCNA and acts distributively to make DNA complementary to an RNA template strand. Consistent with prior S. cerevisiae studies performed in vivo, we propose that Pol ζ is the major DNA Pol that functions in the RNA-templated DSB repair pathway.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"107918"},"PeriodicalIF":5.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500922","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

Identification of the N-terminal residues responsible for the differential microdomain localization of CYP1A1 and CYP1A2. 鉴定导致 CYP1A1 和 CYP1A2 不同微域定位的 N 端残基。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-22 DOI: 10.1016/j.jbc.2024.107891

Robert M Fuchs,James R Reed,J Patrick Connick,Markéta Paloncýová,Martin Šrejber,Petra Čechová,Michal Otyepka,Marilyn K Eyer,Wayne L Backes

{"title":"Identification of the N-terminal residues responsible for the differential microdomain localization of CYP1A1 and CYP1A2.","authors":"Robert M Fuchs,James R Reed,J Patrick Connick,Markéta Paloncýová,Martin Šrejber,Petra Čechová,Michal Otyepka,Marilyn K Eyer,Wayne L Backes","doi":"10.1016/j.jbc.2024.107891","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107891","url":null,"abstract":"The endoplasmic reticulum (ER) is organized into ordered regions enriched in cholesterol and sphingomyelin, and disordered microdomains characterized by more fluidity. Rabbit CYP1A1 and CYP1A2 localize into disordered and ordered microdomains, respectively. Previously, a CYP1A2 chimera containing the first 109 amino acids of CYP1A1 showed altered microdomain localization. The goal of this study was to identify specific residues responsible for CYP1A microdomain localization. Thus, CYP1A2 chimeras containing substitutions from homologous regions of CYP1A1 were expressed in HEK 293T/17 cells, and the localization was examined after solubilization with Brij 98. A CYP1A2 mutant with the three amino acids from CYP1A1 (VAG) at positions 27-29 of CYP1A2 was generated that showed a distribution pattern similar to those of CYP1A1/1A2 chimeras containing both the first 109 amino acids and the first 31 amino acids of CYP1A1 followed by remaining amino acids of CYP1A2. Similarly, the reciprocal substitution of three amino acids from CYP1A2 (AVR) into CYP1A1 resulted in a partial redistribution of the chimera into ordered microdomains. Molecular dynamic simulations indicate that the positive charges of the CYP1A1 and CYP1A2 linker regions between the N-termini and catalytic domains resulted in different depths of immersion of the N-termini in the membrane. The overlap of the distribution of positively charged residues in CYP1A2 (AVR) and negatively charged phospholipids was higher in the ordered than disordered microdomain. These findings identify three residues in the CYP1A N-terminus as a novel microdomain-targeting motif of the P450s and provide a mechanistic explanation for the differential microdomain localization of CYP1A.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"14 1","pages":"107891"},"PeriodicalIF":4.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490377","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

Azotobacter vinelandii scaffold protein NifU transfers iron to NifQ as part of the iron-molybdenum cofactor biosynthesis pathway for nitrogenase. 作为氮酶铁钼辅助因子生物合成途径的一部分，Azotobacter vinelandii 支架蛋白 NifU 将铁转移到 NifQ 上。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-22 DOI: 10.1016/j.jbc.2024.107900

Emma Barahona, Juan Andrés Collantes-García, Elena Rosa-Núñez, Jin Xiong, Xi Jiang, Emilio Jiménez-Vicente, Carlos Echávarri-Erasun, Yisong Guo, Luis M Rubio, Manuel González-Guerrero

{"title":"Azotobacter vinelandii scaffold protein NifU transfers iron to NifQ as part of the iron-molybdenum cofactor biosynthesis pathway for nitrogenase.","authors":"Emma Barahona, Juan Andrés Collantes-García, Elena Rosa-Núñez, Jin Xiong, Xi Jiang, Emilio Jiménez-Vicente, Carlos Echávarri-Erasun, Yisong Guo, Luis M Rubio, Manuel González-Guerrero","doi":"10.1016/j.jbc.2024.107900","DOIUrl":"10.1016/j.jbc.2024.107900","url":null,"abstract":"The Azotobacter vinelandii molybdenum nitrogenase obtains molybdenum from NifQ, a monomeric iron-sulfur molybdoprotein. This protein requires an existing [Fe-S] cluster to form a [Mo-Fe3-S4] group, which acts as a specific molybdenum donor during nitrogenase FeMo-co biosynthesis. Here, we show biochemical evidence supporting the role of NifU as the [Fe-S] cluster donor. Protein-protein interaction studies involving apo-NifQ and as-isolated NifU demonstrated their interaction, which was only effective when NifQ lacked its [Fe-S] cluster. Incubation of apo-NifQ with [Fe4-S4]-loaded NifU increased the iron content of the former, contingent on both proteins being able to interact with one another. As a result of this interaction, a [Fe4-S4] cluster was transferred from NifU to NifQ. In A. vinelandii, NifQ was preferentially metalated by NifU rather than by the [Fe-S] cluster scaffold protein IscU. These results indicate the necessity of co-expressing NifU and NifQ to efficiently provide molybdenum for FeMo-co biosynthesis when engineering nitrogenase in plants.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"107900"},"PeriodicalIF":4.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500917","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

Glycolysis: A multifaceted metabolic pathway and signalling hub. 糖酵解：多方面的代谢途径和信号枢纽

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-21 DOI: 10.1016/j.jbc.2024.107906

Sarah J Kierans,Cormac T Taylor

{"title":"Glycolysis: A multifaceted metabolic pathway and signalling hub.","authors":"Sarah J Kierans,Cormac T Taylor","doi":"10.1016/j.jbc.2024.107906","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107906","url":null,"abstract":"Glycolysis is a highly conserved metabolic pathway responsible for the anaerobic production of adenosine triphosphate (ATP) from the breakdown of glucose molecules. While serving as a primary metabolic pathway in prokaryotes, glycolysis is also utilised by respiring eukaryotic cells, providing pyruvate to fuel oxidative metabolism. Furthermore, glycolysis is the primary source of ATP production in multiple cellular states (e.g. hypoxia) and is particularly important in maintaining bioenergetic homeostasis in the most abundant cell type in the human body, the erythrocyte. Beyond its role in ATP production, glycolysis also functions as a signalling hub, producing several metabolic intermediates which serve roles in both signalling and metabolic processes. These signals emanating from the glycolytic pathway can profoundly impact cell function, phenotype and fate, and have previously been overlooked. In this review, we will discuss the role of the glycolytic pathway as a source of signalling molecules in eukaryotic cells, emphasising the newfound recognition of glycolysis' multifaceted nature and its importance in maintaining cellular homeostasis, beyond its traditional role in ATP synthesis.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"3 1","pages":"107906"},"PeriodicalIF":4.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489554","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

2-Hydroxylation is a chemical switch linking fatty acids to glucose-stimulated insulin secretion. 2-羟化是脂肪酸与葡萄糖刺激的胰岛素分泌之间的化学开关。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-21 DOI: 10.1016/j.jbc.2024.107912

Hong Li,Lin Lin,Xiaoheng Huang,Yang Lu,Xiong Su

{"title":"2-Hydroxylation is a chemical switch linking fatty acids to glucose-stimulated insulin secretion.","authors":"Hong Li,Lin Lin,Xiaoheng Huang,Yang Lu,Xiong Su","doi":"10.1016/j.jbc.2024.107912","DOIUrl":"https://doi.org/10.1016/j.jbc.2024.107912","url":null,"abstract":"Glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is metabolically regulated and progressively diminished during the development of type 2 diabetes (T2D). This dynamic process is tightly coupled with fatty acid metabolism, but the underlying mechanisms remain poorly understood. Fatty acid 2-hydroxylase (FA2H) catalyzes the conversion of fatty acids to chiral specific (R)-2-hydroxy fatty acids ((R)-2-OHFAs), which influences cell metabolism. However, little is known about its potential coupling with GSIS in pancreatic β cells. Here, we showed that Fa2h knockout decreases plasma membrane localization and protein level of glucose transporter 2 (GLUT2), which is essential for GSIS, thereby controlling blood glucose homeostasis. Conversely, FA2H overexpression increases GLUT2 on the plasma membrane and enhances GSIS. Mechanistically, FA2H suppresses the internalization and trafficking of GLUT2 to the lysosomes for degradation. Overexpression of wild-type FA2H, but not its mutant with impaired hydroxylase activity in the pancreatic β-cells, improves glucose tolerance by promoting insulin secretion. Levels of 2-OHFAs and Fa2h gene expression are lower in high-fat diet-induced obese mouse islets with impaired GSIS. Moreover, lower gene expression of FA2H is observed in a set of human T2D islets when the insulin secretion index is significantly suppressed, indicating the potential involvement of FA2H in regulating mouse and human GSIS. Collectively, our results identified an FA chemical switch to maintain the proper response of GSIS in pancreatic β cells and provided a new perspective on the β-cell failure that triggers T2D.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"14 1","pages":"107912"},"PeriodicalIF":4.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489508","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

Alpha-1-B glycoprotein (A1BG) inhibits sterol-binding and export by CRISP2. α-1-B糖蛋白（A1BG）通过CRISP2抑制固醇的结合和输出。

IF 5.4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-19 DOI: 10.1016/j.jbc.2024.107910

Ola El Atab, Barkha Gupta, Zhu Han, Jiri Stribny, Oluwatoyin A Asojo, Roger Schneiter

{"title":"Alpha-1-B glycoprotein (A1BG) inhibits sterol-binding and export by CRISP2.","authors":"Ola El Atab, Barkha Gupta, Zhu Han, Jiri Stribny, Oluwatoyin A Asojo, Roger Schneiter","doi":"10.1016/j.jbc.2024.107910","DOIUrl":"10.1016/j.jbc.2024.107910","url":null,"abstract":"Proteins belonging to the CAP superfamily are present in all kingdoms of life and have been implicated in various processes, including sperm maturation and cancer progression. They are mostly secreted glycoproteins and share a unique conserved CAP domain. The precise mode of action of these proteins, however, has remained elusive. Saccharomyces cerevisiae expresses three members of this protein family, which bind sterols in vitro and promote sterol secretion from cells. This sterol-binding and export function of yeast Pry proteins is conserved in the mammalian cysteine-rich secretory protein (CRISP) proteins and other CAP superfamily members. CRISP3 is an abundant protein of the human seminal plasma and interacts with alpha-1-B glycoprotein (A1BG), a human plasma glycoprotein that is upregulated in different types of cancers. Here, we examined whether the interaction between CRISP proteins and A1BG affects the sterol-binding function of CAP family members. Coexpression of A1BG with CAP proteins abolished their sterol export function in yeast and their interaction inhibits sterol-binding in vitro. We map the interaction between A1BG and CRISP2 to the third of five repeated immunoglobulin-like domains within A1BG. Interestingly, the interaction between A1BG and CRISP2 requires magnesium, suggesting that coordination of Mg2+ by the highly conserved tetrad residues within the CAP domain is essential for a stable interaction between the two proteins. The observation that A1BG modulates the sterol-binding function of CRISP2 has potential implications for the role of A1BG and related immunoglobulin-like domain containing proteins in cancer progression and the toxicity of reptile venoms containing CRISP proteins.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"107910"},"PeriodicalIF":5.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466203","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

Complex sporulation-specific expression of transcription termination factor Rho highlights its involvement in Bacillus subtilis cell differentiation. 转录终止因子 Rho 的复杂孢子特异性表达突显了它在枯草杆菌细胞分化中的参与。

IF 5.4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-19 DOI: 10.1016/j.jbc.2024.107905

Vladimir Bidnenko, Arnaud Chastanet, Christine Péchoux, Yulia Redko-Hamel, Olivier Pellegrini, Sylvain Durand, Ciarán Condon, Marc Boudvillain, Matthieu Jules, Elena Bidnenko

{"title":"Complex sporulation-specific expression of transcription termination factor Rho highlights its involvement in Bacillus subtilis cell differentiation.","authors":"Vladimir Bidnenko, Arnaud Chastanet, Christine Péchoux, Yulia Redko-Hamel, Olivier Pellegrini, Sylvain Durand, Ciarán Condon, Marc Boudvillain, Matthieu Jules, Elena Bidnenko","doi":"10.1016/j.jbc.2024.107905","DOIUrl":"10.1016/j.jbc.2024.107905","url":null,"abstract":"Termination factor Rho, responsible for the main factor-dependent pathway of transcription termination and the major inhibitor of antisense transcription, is an emerging regulator of various physiological processes in microorganisms. In Gram-positive bacterium Bacillus subtilis, Rho is involved in the control of cell adaptation to starvation and, in particular, in the control of sporulation, a complex differentiation program leading to the formation of a highly resistant dormant spore. While the initiation of sporulation requires a decrease in Rho protein levels during the transition to stationary phase, the mechanisms regulating the expression of rho gene throughout the cell cycle remain largely unknown. Here we show that a drop in the activity of the vegetative SigA-dependent rho promoter causes the inhibition of rho expression in stationary phase. However, after the initiation of sporulation, rho gene is specifically reactivated in two compartments of the sporulating cell using distinct mechanisms. In the mother cell, rho expression occurs by read-through transcription initiated at the SigH-dependent promoter of the distal spo0F gene. In the forespore, rho gene is transcribed from the intrinsic promoter recognized by the alternative sigma factor SigF. These regulatory elements ensure the activity of Rho during sporulation, which appears important for the proper formation of spores. We provide experimental evidence that disruption of the spatiotemporal expression of rho during sporulation affects the resistance properties of spores, their morphology, and the ability to return to vegetative growth under favorable growth conditions.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"107905"},"PeriodicalIF":5.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466204","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

Targeting chaperone modifications: Innovative approaches to cancer treatment. 靶向伴侣修饰：癌症治疗的创新方法

IF 5.4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-19 DOI: 10.1016/j.jbc.2024.107907

Mariah Stewart, Jonathan C Schisler

{"title":"Targeting chaperone modifications: Innovative approaches to cancer treatment.","authors":"Mariah Stewart, Jonathan C Schisler","doi":"10.1016/j.jbc.2024.107907","DOIUrl":"10.1016/j.jbc.2024.107907","url":null,"abstract":"Cancer and other chronic diseases are marked by alterations in the protein quality control system, affecting the posttranslational destiny of various proteins that regulate, structure, and catalyze cellular processes. Cellular chaperones, also known as heat shock proteins (HSPs), are pivotal in this system, performing protein triage that often determines the fate of proteins they bind to. Grasping the regulatory mechanisms of HSPs and their associated cofactors is crucial for understanding protein quality control in both healthy and diseased states. Recent research has shed light on the interactions within the protein quality control system and how post-translational modification govern protein interactions, function, and localization, which can drive or inhibit cell proliferation. This body of work encompasses critical elements of the heat shock response, including heat shock protein 70, heat shock protein 90, carboxyl-terminus of HSC70 interacting protein, and heat shock protein organizing protein. This review aims to synthesize these advancements, offering a holistic understanding of the system and its response when commandeered by diseases like cancer. We focus on the mechanistic shift in co-chaperone engagement-transitioning from heat shock protein organizing protein to carboxyl-terminus of HSC70 interacting protein in association with heat shock protein 70 and heat shock protein 90-which could influence cellular growth and survival pathways. A comprehensive examination of posttranslational modification-driven regulation within the protein quality control network is presented, highlighting the roles of activation factors, chaperones, and co-chaperones. Our insights aim to inform new strategies for therapeutically targeting diseases by considering the entire heat shock response system.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"107907"},"PeriodicalIF":5.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466211","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

Fragility of ER homeostatic regulation underlies haploid instability in human somatic cells. 人类体细胞单倍体不稳定性的根源在于ER平衡调节的脆弱性。

IF 5.4 2区生物学

Journal of Biological Chemistry Pub Date : 2024-10-19 DOI: 10.1016/j.jbc.2024.107909

Sumire Ishida-Ishihara, Kan Yaguchi, Sena Miura, Ryoto Nomura, QiJiao Wang, Koya Yoshizawa, Kimino Sato, Guang Yang, Krisztina Veszelyi, Gabor Banhegyi, Eva Margittai, Ryota Uehara

{"title":"Fragility of ER homeostatic regulation underlies haploid instability in human somatic cells.","authors":"Sumire Ishida-Ishihara, Kan Yaguchi, Sena Miura, Ryoto Nomura, QiJiao Wang, Koya Yoshizawa, Kimino Sato, Guang Yang, Krisztina Veszelyi, Gabor Banhegyi, Eva Margittai, Ryota Uehara","doi":"10.1016/j.jbc.2024.107909","DOIUrl":"10.1016/j.jbc.2024.107909","url":null,"abstract":"Mammalian somatic cells are generally unstable in the haploid state, resulting in haploid-to-diploid conversion within a short time frame. However, cellular and molecular principles that limit the sustainability of somatic haploidy remain unknown. In this study, we found the haploidy-linked vulnerability to endoplasmic reticulum (ER) stress as a critical cause of haploid intolerance in human somatic cells. Pharmacological induction of ER stress selectively induced apoptosis in haploid cells, facilitating the replacement of haploids by coexisting diploidized cells in a caspase-dependent manner. Biochemical analyses revealed that unfolded protein response (UPR) was activated with similar dynamics between haploids and diploids upon ER stress induction. However, haploids were less efficient in solving proteotoxic stress, resulting in a bias toward a proapoptotic mode of UPR signaling. Artificial replenishment of chaperone function substantially alleviated the haploidy-linked upregulation of proapoptotic signaling and improved haploid cell retention under tunicamycin-induced ER stress. These data demonstrate that the ER stress-driven haploid instability stems from inefficient proteostatic control that alters the functionality of UPR to cause apoptosis selectively in haploids. Interestingly, haploids suffered a higher level of protein aggregation even in unperturbed conditions, and the long-term stability of the haploid state was significantly improved by alleviating their natural proteotoxicity. Based on these results, we propose that the haploidy-specific vulnerability to ER stress creates a fundamental cause of haploid intolerance in mammalian somatic cells. Our findings provide new insight into the principle that places a stringent restriction on the evolution of animal life cycles.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"107909"},"PeriodicalIF":5.4,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466207","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