Molecular and Cellular Biology最新文献_第8页

Key Mechanisms in Lysosome Stability, Degradation and Repair. 溶酶体稳定性、降解和修复的关键机制。

IF 2.8 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-05-09 DOI: 10.1080/10985549.2025.2494762

Rui Zhang, Marc A Vooijs, Tom Gh Keulers

{"title":"Key Mechanisms in Lysosome Stability, Degradation and Repair.","authors":"Rui Zhang, Marc A Vooijs, Tom Gh Keulers","doi":"10.1080/10985549.2025.2494762","DOIUrl":"10.1080/10985549.2025.2494762","url":null,"abstract":"Lysosomes are organelles that play pivotal roles in macromolecule digestion, signal transduction, autophagy, and cellular homeostasis. Lysosome instability, including the inhibition of lysosomal intracellular activity and the leakage of their contents, is associated with various pathologies, including cancer, neurodegenerative diseases, inflammatory diseases and infections. These lysosomal-related pathologies highlight the significance of factors contributing to lysosomal dysfunction. The vulnerability of the lysosomal membrane and its components to internal and external stimuli make lysosomes particularly susceptible to damage. Cells are equipped with mechanisms to repair or degrade damaged lysosomes to prevent cell death. Understanding the factors influencing lysosome stabilization and damage repair is essential for developing effective therapeutic interventions for diseases. This review explores the factors affecting lysosome acidification, membrane integrity, and functional homeostasis and examines the underlying mechanisms of lysosomal damage repair. In addition, we summarize how various risk factors impact lysosomal activity and cell fate.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"212-224"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018298","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

Erythropoietin Production in Embryonic Neural Cells is Controlled by Hypoxia Signaling and Histone Deacetylases with an Undifferentiated Cellular State. 胚胎神经细胞中促红细胞生成素的产生受缺氧信号和未分化细胞状态组蛋白去乙酰化酶的控制。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2024-12-02 DOI: 10.1080/10985549.2024.2428717

Yuma Iwamura, Taku Nakai, Koichiro Kato, Hirotaka Ishioka, Masayuki Yamamoto, Ikuo Hirano, Norio Suzuki

{"title":"Erythropoietin Production in Embryonic Neural Cells is Controlled by Hypoxia Signaling and Histone Deacetylases with an Undifferentiated Cellular State.","authors":"Yuma Iwamura, Taku Nakai, Koichiro Kato, Hirotaka Ishioka, Masayuki Yamamoto, Ikuo Hirano, Norio Suzuki","doi":"10.1080/10985549.2024.2428717","DOIUrl":"10.1080/10985549.2024.2428717","url":null,"abstract":"During mammalian development, production sites of the erythroid growth factor erythropoietin (EPO) shift from the neural tissues to the liver in embryos and to the kidneys in adults. Embryonic neural EPO-producing (NEP) cells, a subpopulation of neuroepithelial and neural crest cells, express the Epo gene between embryonic day (E) 8.5 and E11.5 to promote primitive erythropoiesis in mice. While Epo gene expression in the liver and kidneys is induced under hypoxic conditions through hypoxia-inducible transcription factors (HIFs), the Epo gene regulatory mechanisms in NEP cells remain to be elucidated. Here, we confirmed the presence of cells co-expressing EPO and HIFs in mouse neural tubes, where the hypoxic microenvironment activates HIFs. Chemical activation and inhibition of HIFs demonstrated the hypoxic regulation of EPO expression in human fetal neural progenitors and mouse embryonic neural tissues. In addition, we found that histone deacetylase inhibitors can reactivate EPO production in cell lines derived from NEP cells and human neuroblastoma, as well as in mouse primary neural crest cells, while rejuvenating these cells. Furthermore, the ability of the rejuvenated cells to produce EPO was maintained in hypoxia. Thus, EPO production is controlled by epigenetic mechanisms and hypoxia signaling in the immature state of hypoxic NEP cells.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"32-45"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770614","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 Mutation in the RNA-Binding Protein Cth2 Limits the Adaptation of a Subset of Wild Saccharomyces cerevisiae Yeast Strains to Iron Deficiency. rna结合蛋白Cth2的突变限制了野生酿酒酵母菌株对铁缺乏的适应。

IF 2.8 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-08-04 DOI: 10.1080/10985549.2025.2539754

Elena Valera-García, Raquel Sorribes-Dauden, Sergi Puig

{"title":"A Mutation in the RNA-Binding Protein Cth2 Limits the Adaptation of a Subset of Wild Saccharomyces cerevisiae Yeast Strains to Iron Deficiency.","authors":"Elena Valera-García, Raquel Sorribes-Dauden, Sergi Puig","doi":"10.1080/10985549.2025.2539754","DOIUrl":"10.1080/10985549.2025.2539754","url":null,"abstract":"Iron is an essential micronutrient for eukaryotic organisms. In response to iron deficiency, the yeast Saccharomyces cerevisiae optimizes iron utilization by downregulating nonessential iron-dependent processes, such as mitochondrial respiration. This regulatory mechanism is mediated by a mRNA-binding protein designated Cth2. In response to iron scarcity, Cth2 binds through its tandem zinc-finger (TFZ) domain to multiple mRNAs encoding proteins that are necessary for iron-dependent pathways. This binding limits the expression of these mRNAs by promoting their degradation and inhibiting their translation. In this study, we have examined a set of wild yeast strains that share a G195R mutation within the Cth2 TZF domain. By genetically editing both laboratory and wild yeast strains, we demonstrate that the Cth2-G195R protein is defective in binding and degradation of its target transcripts, and it accumulates in the nucleus of the cell, leading to a significant growth defect in iron-deficient conditions. Some of these wild yeast strains also display enhanced tolerance to high iron conditions, indicating that they have adapted to environments with elevated iron levels and have consequently diminished their capacity to grow in iron-limiting conditions. These findings highlight the crucial function of Cth2 in enabling yeast cells to adapt to iron-deficient environments.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"561-575"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775802","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

Lactate as an Exercise Mimetic: Mitigating Disuse Atrophy and Improving Muscle Endurance in Aging SAMP8 Mice. 乳酸作为运动模拟物：减轻衰老SAMP8小鼠的废用性萎缩和提高肌肉耐力。

IF 2.8 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-09-17 DOI: 10.1080/10985549.2025.2551616

Zhen Qi, Xi Liu, Yifen Chen, Linglin Zhang, Longhe Yang, Caihua Huang, Donghai Lin

{"title":"Lactate as an Exercise Mimetic: Mitigating Disuse Atrophy and Improving Muscle Endurance in Aging SAMP8 Mice.","authors":"Zhen Qi, Xi Liu, Yifen Chen, Linglin Zhang, Longhe Yang, Caihua Huang, Donghai Lin","doi":"10.1080/10985549.2025.2551616","DOIUrl":"10.1080/10985549.2025.2551616","url":null,"abstract":"Lactate, historically considered a metabolic byproduct, has emerged as a key regulator of muscle physiology and metabolism. This study explores its potential as an exercise mimetic to counteract disuse muscle atrophy (DMA) in aging skeletal muscle using a hindlimb suspension model in senescence-accelerated prone 8 (SAMP8) mice. The mice were divided into four groups: Control, lactate-treated control, hindlimb suspension, and hindlimb suspension with lactate intervention. Lactate administration preserved gastrocnemius muscle mass, restored muscle strength, and attenuated oxidative fiber atrophy. Electrophoretic and histological analyses showed increased MyHC I expression, indicating protection of oxidative fibers. Functional assessments revealed improved muscle endurance and contractile force, while metabolomic profiling identified changes in energy metabolism, amino acid metabolism, and protein synthesis pathways. Specifically, lactate improved impaired branched-chain amino acid metabolism, suggesting enhanced protein synthesis. In addition, lactate boosted Cori cycle activity, upregulated hepatic lactate transporters, and increased lactate dehydrogenase B activity, facilitating efficient lactate metabolism and gluconeogenesis. These results provide new insights into the role of lactate as a metabolic regulator and highlight its potential as a therapeutic intervention to combat exercise-induced muscle wasting and preserve muscle function in aging and immobilized individuals.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"511-529"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075818","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

Understanding the Impact of Mutations in the Cystathionine Beta-Synthase Gene: Towards Novel Therapeutics for Homocystinuria. 了解胱氨酸-合成酶基因突变的影响：探索同型半胱氨酸尿的新疗法。

IF 2.8 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-06-10 DOI: 10.1080/10985549.2025.2511338

Tomas Majtan, Ela Mijatovic, Maria Petrosino

{"title":"Understanding the Impact of Mutations in the Cystathionine Beta-Synthase Gene: Towards Novel Therapeutics for Homocystinuria.","authors":"Tomas Majtan, Ela Mijatovic, Maria Petrosino","doi":"10.1080/10985549.2025.2511338","DOIUrl":"10.1080/10985549.2025.2511338","url":null,"abstract":"Protein misfolding and conformational instability drive protein conformational disorders, causing either accelerated degradation and loss-of-function, as in inherited metabolic disorders like lysosomal storage disorders, or toxic aggregation and gain-of-function, as in neurodegenerative diseases like Alzheimer's disease or amyotrophic lateral sclerosis. Classical homocystinuria (HCU), an inborn error of sulfur amino acid metabolism, results from cystathionine beta-synthase (CBS) deficiency. CBS regulates methionine conversion into metabolites critical for redox balance (cysteine, glutathione) and signaling (H2S). Pathogenic missense mutations in the CBS gene often impair folding, cofactor binding, stability or oligomerization rather than targeting the key catalytic residues of the CBS enzyme. Advances in understanding of CBS folding and assembly as well as CBS interactions with cellular proteostasis network offer potential for therapies using pharmacological chaperones (PCs), i.e., compounds facilitating proper folding, assembly or cellular trafficking. This review discusses progress in identifying PCs for HCU, including chemical chaperones, cofactors, and proteasome inhibitors. We outline future directions, focusing on high-throughput screening and structure-based drug design to develop CBS-specific PCs. These could stabilize mutant CBS, enhance its stability and restore activity, providing new treatments for HCU and possibly other conditions related to dysregulated CBS, such as cancer or Down's syndrome.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"327-342"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266709","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

ALYREF Promotes Progression of Intrahepatic Cholangiocarcinoma through Increasing the Level of Isocitrate Dehydrogenase 1 in an m5C-Dependent Manner. ALYREF通过以m5c依赖的方式增加异柠檬酸脱氢酶1的水平，促进肝内胆管癌的进展。

IF 2.8 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-05-14 DOI: 10.1080/10985549.2025.2490031

Zhiqiang Hao, Haixiang Yang, Wei Zhu, Dedong Yu, Yanjie Cao, Yun Wu

{"title":"ALYREF Promotes Progression of Intrahepatic Cholangiocarcinoma through Increasing the Level of Isocitrate Dehydrogenase 1 in an m5C-Dependent Manner.","authors":"Zhiqiang Hao, Haixiang Yang, Wei Zhu, Dedong Yu, Yanjie Cao, Yun Wu","doi":"10.1080/10985549.2025.2490031","DOIUrl":"10.1080/10985549.2025.2490031","url":null,"abstract":"RNA 5-methylcytosine (m5C) modification has emerged as an important regulatory mechanism in the progression of human cancers, including hepatobiliary tumors. The m5C \"reader\" Aly/REF export factor (ALYREF) was recently found to be identified as a prognostic biomarker in liver cancer. However, its exact role in intrahepatic cholangiocarcinoma (ICC) progression is unclear. In this study, ALYREF was found to be upregulated in ICC tissues and cells. The gain- and loss-of-function experiments indicated that ALYREF promoted cell proliferation and invasion and suppressed cell apoptosis. Moreover, we found that isocitrate dehydrogenase 1 (IDH1), a metastatic marker of liver cancer, was also upregulated in ICC tissues, displayed a relatively strong positive correlation with the level of ALYREF, and was positively regulated by ALYREF. As an m5C \"reader\", ALYREF interacted with m5C-IDH1 mRNA and increased its stability. ALYREF knockdown partially eliminated the promotion of IDH1 on ICC cell proliferation and invasion. ALYREF positively regulated NRF2-driven glutathione synthesis in ICC cells, which was reversed by IDH1 silencing. Finally, in a xenograft tumor mouse model, knockdown of ALYREF or treatment with ivosidenib (an IDH1 inhibitor) significantly suppressed tumor growth in vivo. In conclusion, ALYREF promotes ICC progression by increasing IDH1 levels in an m5C-dependent manner.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"45 5","pages":"198-211"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079054","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

Loss of Function Mouse Models Reveal a Novel Regulatory Function for ULK1 in Myeloproliferative Neoplasms. 功能缺失小鼠模型揭示了ULK1在骨髓增殖性肿瘤中的一种新的调节功能。

IF 2.8 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-07-23 DOI: 10.1080/10985549.2025.2529837

Diana Saleiro, Jeremy Q Wen, Markella Zannikou, Brian Lee, Ewa M Kosciuczuk, Sarah D Nehlsen, Adam Munshi, Xintong Chen, Chidera V Oku, Briana Hryhorysak, Jamie N Guillen Magaña, Jorge Heneche, Mariafausta Fischietti, Liliana Ilut, Sara H Small, Anitria Cotton, Trent Hall, Monique A Payton, Elspeth M Beauchamp, Feng Yue, Masha Kocherginsky, Elizabeth T Bartom, Ronald Hoffman, John D Crispino, Leonidas C Platanias

{"title":"Loss of Function Mouse Models Reveal a Novel Regulatory Function for ULK1 in Myeloproliferative Neoplasms.","authors":"Diana Saleiro, Jeremy Q Wen, Markella Zannikou, Brian Lee, Ewa M Kosciuczuk, Sarah D Nehlsen, Adam Munshi, Xintong Chen, Chidera V Oku, Briana Hryhorysak, Jamie N Guillen Magaña, Jorge Heneche, Mariafausta Fischietti, Liliana Ilut, Sara H Small, Anitria Cotton, Trent Hall, Monique A Payton, Elspeth M Beauchamp, Feng Yue, Masha Kocherginsky, Elizabeth T Bartom, Ronald Hoffman, John D Crispino, Leonidas C Platanias","doi":"10.1080/10985549.2025.2529837","DOIUrl":"10.1080/10985549.2025.2529837","url":null,"abstract":"Defining the mechanisms that promote development and progression of myeloproliferative neoplasms (MPNs) is important for understanding the mechanisms of malignant hematopoiesis and critical development of new treatment approaches. We provide evidence for a key and essential role of the kinase ULK1 in MPN pathophysiology. Our studies demonstrate that genetic or pharmacological targeting of ULK1 delays substantially disease development in Jak2V617F-mutant MPN models in vivo and establish that ULK1 activity is required for transcription of genes that control hematopoietic stem cell differentiation. Pharmacological targeting of ULK1 exhibits potent therapeutic effects, resulting in reduction of early stage erythroid progenitors in spleen and bone marrow, decreased levels of hemoglobin, and reduced spleen size in MPN mouse models in vivo. Taken together, these findings provide the first evidence for a novel protumorigenic role for ULK1 downstream of the hyperactive JAK2 signaling in MPNs and raise the potential of ULK1 as a new therapeutic target for the treatment of MPNs.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"395-418"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12645588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144690901","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

Molecular Insights into the Pathophysiology of Dysregulated Erythropoiesis: The Crucial Role of Iron Homeostasis. 红细胞生成异常病理生理的分子洞察：铁稳态的关键作用。

IF 2.8 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-09-10 DOI: 10.1080/10985549.2025.2553648

Tohru Fujiwara, Hideo Harigae

{"title":"Molecular Insights into the Pathophysiology of Dysregulated Erythropoiesis: The Crucial Role of Iron Homeostasis.","authors":"Tohru Fujiwara, Hideo Harigae","doi":"10.1080/10985549.2025.2553648","DOIUrl":"10.1080/10985549.2025.2553648","url":null,"abstract":"Erythropoiesis, i.e., process of red blood cell (RBC) production, is highly dependent on iron, with 60-70% of the total body iron incorporated into hemoglobin. Iron homeostasis is tightly regulated, given that both iron overload and deficiency can impair RBC development and function. Iron-loading anemias, such as sideroblastic anemia and thalassemia, are associated with ineffective erythropoiesis and systemic iron overload. Recent studies also highlight the role of ferroptosis, i.e., iron-dependent cell death, in erythroid failure under conditions of iron overload. Transcriptional repressor BTB and CNC homology 1 (BACH1), which is regulated by intracellular heme, is a potential key mediator of ferroptosis. In iron deficiency, limited iron availability impairs heme and globin biosynthesis, mitochondrial function, and erythropoietin responsiveness, while also inducing widespread changes in gene expression through DNA methylation, all of which contribute to dysregulated erythropoiesis. Under iron deficiency, BACH1 plays a critical role in maintaining the balance between heme and globin by suppressing globin gene expression, thereby preventing the aggregation of toxic non-heme globin. This review summarizes the current understanding of the mechanisms by which iron imbalance contributes to erythropoietic failure and highlights BACH1 as a potential integrative regulator in the pathophysiology of anemia in both iron-overload and iron-deficient states.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"547-560"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030057","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 and Orientation Dependent CTCF Binding Determines VDJ Recombination at Murine Tcrb Locus. 位点特异性和定向依赖性CTCF结合决定小鼠Tcrb位点的VDJ重组。

IF 2.8 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-09-18 DOI: 10.1080/10985549.2025.2553650

Monika Yadav, Samriddhi Sharma, S R Rajalekshmi, Nidhi Bhasin, Jeanne Yimdjo, Karl Pfeifer, Madhulika Srivastava

{"title":"Site Specific and Orientation Dependent CTCF Binding Determines VDJ Recombination at Murine Tcrb Locus.","authors":"Monika Yadav, Samriddhi Sharma, S R Rajalekshmi, Nidhi Bhasin, Jeanne Yimdjo, Karl Pfeifer, Madhulika Srivastava","doi":"10.1080/10985549.2025.2553650","DOIUrl":"10.1080/10985549.2025.2553650","url":null,"abstract":"CTCF is a multifunctional protein that mediates long-range cis-DNA interactions in mammalian genomes. Chromatin architecture governs spatial and functional interactions of gene regulatory elements at various loci and is impacted by the ability of CTCF to restrict cohesin complex dependent chromatin extrusion. In addition, at antigen receptor loci, long-range interactions facilitate spatial proximity of gene segments for VDJ recombination that generates functional genes encoding immunoglobulins and T-cell receptors in developing lymphocytes. To investigate the role of CTCF in VDJ recombination, we mutated CTCF binding sites (CBS) of murine Tcrb locus. Our analysis revealed that CBS interspersed in the domain encompassing variable gene segments (Vb) are not redundant. They exhibit independent but additive effects on dynamic chromatin organization leading to distinct VDJ recombination profiles in CBS mutants depending on positions of mutated CBS relative to Vb segments. Further, inversion of a single CBS drastically altered the chromatin loop organization and VDJ recombination profile. Our results demonstrate the critical importance of chromatin extrusion for generation of chromatin loops for VDJ recombination and underscore its dynamic impediment by CTCF binding at specific points within Vb segment domain to be essential to diversify the usage of Vb segments for VDJ recombination at Tcrb locus.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"530-546"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081065","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

Nuclear Roles for Canonically Lysosomal Proteases. 典型溶酶体蛋白酶的核作用。

IF 2.8 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-06-22 DOI: 10.1080/10985549.2025.2519158

Anna E Enneking, Marc M Khorey, Laura E Edgington-Mitchell

{"title":"Nuclear Roles for Canonically Lysosomal Proteases.","authors":"Anna E Enneking, Marc M Khorey, Laura E Edgington-Mitchell","doi":"10.1080/10985549.2025.2519158","DOIUrl":"10.1080/10985549.2025.2519158","url":null,"abstract":"While the cysteine proteases legumain and cathepsins have traditionally been known as \"lysosomal\" proteases, there is increasing evidence to suggest that they also contribute to a wide range of extralysosomal processes, including in the nucleus. This review aims to provide a comprehensive overview of the current knowledge regarding the translocation of these proteases to the nucleus and their functions on arrival. We discuss possible mechanisms for transporting these proteases to the nucleus, including the presence of a nuclear localization signal sequence or hitchhiking on other proteins that possess this sequence. This transport requires the proteases to first reach the cytosol, which may occur via direct cytosolic translation of truncated proteases or downstream of lysosomal membrane permeabilization. We also discuss the evidence for functions of these proteases upon arrival to the nucleus, including cell cycle progression, cell differentiation, cell death, immune regulation, and epigenetic regulation. As protease substrate profiling methods continue to improve, it is anticipated that many new nuclear substrates and interacting partners will be identified to reveal additional functions for nuclear proteases.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"343-352"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369067","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