Life Science Alliance最新文献_第5页

Chaperone BiP controls ER stress sensor Ire1 through interactions with its oligomers. 蛋白伴侣 BiP 通过与其寡聚体的相互作用控制 ER 应激传感器 Ire1。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-05 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402702

Sam Dawes, Nicholas Hurst, Gabriel Grey, Lukasz Wieteska, Nathan V Wright, Iain W Manfield, Mohammed H Hussain, Arnout P Kalverda, Jozef R Lewandowski, Beining Chen, Anastasia Zhuravleva

{"title":"Chaperone BiP controls ER stress sensor Ire1 through interactions with its oligomers.","authors":"Sam Dawes, Nicholas Hurst, Gabriel Grey, Lukasz Wieteska, Nathan V Wright, Iain W Manfield, Mohammed H Hussain, Arnout P Kalverda, Jozef R Lewandowski, Beining Chen, Anastasia Zhuravleva","doi":"10.26508/lsa.202402702","DOIUrl":"10.26508/lsa.202402702","url":null,"abstract":"The complex multistep activation cascade of Ire1 involves changes in the Ire1 conformation and oligomeric state. Ire1 activation enhances ER folding capacity, in part by overexpressing the ER Hsp70 molecular chaperone BiP; in turn, BiP provides tight negative control of Ire1 activation. This study demonstrates that BiP regulates Ire1 activation through a direct interaction with Ire1 oligomers. Particularly, we demonstrated that the binding of Ire1 luminal domain (LD) to unfolded protein substrates not only trigger conformational changes in Ire1-LD that favour the formation of Ire1-LD oligomers but also exposes BiP binding motifs, enabling the molecular chaperone BiP to directly bind to Ire1-LD in an ATP-dependent manner. These transient interactions between BiP and two short motifs in the disordered region of Ire1-LD are reminiscent of interactions between clathrin and another Hsp70, cytoplasmic Hsc70. BiP binding to substrate-bound Ire1-LD oligomers enables unfolded protein substrates and BiP to synergistically and dynamically control Ire1-LD oligomerisation, helping to return Ire1 to its deactivated state when an ER stress response is no longer required.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893775","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

Activation mechanism and novel binding sites of the BK_Ca channel activator CTIBD. BKCa 通道激活剂 CTIBD 的激活机制和新的结合位点。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-08-01 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402621

Narasaem Lee, Subin Kim, Na Young Lee, Heeji Jo, Pyeonghwa Jeong, Haushabhau S Pagire, Suvarna H Pagire, Jin Hee Ahn, Mi Sun Jin, Chul-Seung Park

{"title":"Activation mechanism and novel binding sites of the BKCa channel activator CTIBD.","authors":"Narasaem Lee, Subin Kim, Na Young Lee, Heeji Jo, Pyeonghwa Jeong, Haushabhau S Pagire, Suvarna H Pagire, Jin Hee Ahn, Mi Sun Jin, Chul-Seung Park","doi":"10.26508/lsa.202402621","DOIUrl":"10.26508/lsa.202402621","url":null,"abstract":"The large-conductance calcium-activated potassium (BKCa) channel, which is crucial for urinary bladder smooth muscle relaxation, is a potential target for overactive bladder treatment. Our prior work unveiled CTIBD as a promising BKCa channel activator, altering V 1/2 and G max This study investigates CTIBD's activation mechanism, revealing its independence from the Ca2+ and membrane voltage sensing of the BKCa channel. Cryo-electron microscopy disclosed that two CTIBD molecules bind to hydrophobic regions on the extracellular side of the lipid bilayer. Key residues (W22, W203, and F266) are important for CTIBD binding, and their replacement with alanine reduces CTIBD-mediated channel activation. The triple-mutant (W22A/W203A/F266A) channel showed the smallest V 1/2 shift with a minimal impact on activation and deactivation kinetics by CTIBD. At the single-channel level, CTIBD treatment was much less effective at increasing P o in the triple mutant, mainly because of a drastically increased dissociation rate compared with the WT. These findings highlight CTIBD's mechanism, offering crucial insights for developing small-molecule treatments for BKCa-related pathophysiological conditions.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875271","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

Rit1-TBC1D10B signaling modulates FcγR-mediated phagosome formation in RAW264 macrophages. Rit1-TBC1D10B 信号调节 RAW264 巨噬细胞中 FcγR 介导的吞噬体形成。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-07-31 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402651

Youhei Egami, Katsuhisa Kawai, Nobukazu Araki

{"title":"Rit1-TBC1D10B signaling modulates FcγR-mediated phagosome formation in RAW264 macrophages.","authors":"Youhei Egami, Katsuhisa Kawai, Nobukazu Araki","doi":"10.26508/lsa.202402651","DOIUrl":"10.26508/lsa.202402651","url":null,"abstract":"Phagocytosis is an important immune response that protects the host from pathogen invasion. Rit1 GTPase is known to be involved in diverse cellular processes. However, its role in FcγR-mediated phagocytosis remains unclear. Our live-cell imaging analysis revealed that Rit1 was localized to the membranes of F-actin-rich phagocytic cups in RAW264 macrophages. Rit1 knockout and expression of the GDP-locked Rit1 mutant suppressed phagosome formation. We also found that TBC1D10B, a GAP for the Rab family GTPases, colocalizes with Rit1 in the membranes of phagocytic cups. Expression and knockout studies have shown that TBC1D10B decreases phagosome formation in both Rab-GAP activity-dependent and -independent manners. Notably, the expression of the GDP-locked Rit1 mutant or Rit1 knockout inhibited the dissociation of TBC1D10B from phagocytic cups. In addition, the expression of the GTP-locked Rit1 mutant promoted the dissociation of TBC1D10B in phagocytic cups and restored the rate of phagosome formation in TBC1D10B-expressing cells. These data suggest that Rit1-TBC1D10B signaling regulates FcγR-mediated phagosome formation in macrophages.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860198","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

Differential roles of lysosomal cholesterol transporters in the development of C. elegans NMJs. 溶酶体胆固醇转运体在秀丽隐杆线虫 NMJ 发育过程中的不同作用

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-07-31 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402584

Amin Guo, Qi Wu, Xin Yan, Kanghua Chen, Yuxiang Liu, Dingfa Liang, Yuxiao Yang, Qunfeng Luo, Mingtao Xiong, Yong Yu, Erkang Fei, Fei Chen

{"title":"Differential roles of lysosomal cholesterol transporters in the development of C. elegans NMJs.","authors":"Amin Guo, Qi Wu, Xin Yan, Kanghua Chen, Yuxiang Liu, Dingfa Liang, Yuxiao Yang, Qunfeng Luo, Mingtao Xiong, Yong Yu, Erkang Fei, Fei Chen","doi":"10.26508/lsa.202402584","DOIUrl":"10.26508/lsa.202402584","url":null,"abstract":"Cholesterol homeostasis in neurons is critical for synapse formation and maintenance. Neurons with impaired cholesterol uptake undergo progressive synapse loss and eventual degeneration. To investigate the molecular mechanisms of neuronal cholesterol homeostasis and its role during synapse development, we studied motor neurons of Caenorhabditis elegans because these neurons rely on dietary cholesterol. Combining lipidomic analysis, we discovered that NCR-1, a lysosomal cholesterol transporter, promotes cholesterol absorption and synapse development. Loss of ncr-1 causes smaller synapses, and low cholesterol exacerbates the deficits. Moreover, NCR-1 deficiency hinders the increase in synapses under high cholesterol. Unexpectedly, NCR-2, the NCR-1 homolog, increases the use of cholesterol and sphingomyelins and impedes synapse formation. NCR-2 deficiency causes an increase in synapses regardless of cholesterol concentration. Inhibiting the degradation or synthesis of sphingomyelins can induce or suppress the synaptic phenotypes in ncr-2 mutants. Our findings indicate that neuronal cholesterol homeostasis is differentially controlled by two lysosomal cholesterol transporters and highlight the importance of neuronal cholesterol homeostasis in synapse development.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860197","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

Golgi pH homeostasis stabilizes the lysosomal membrane through N-glycosylation of membrane proteins. 高尔基体 pH 平衡通过膜蛋白的 N-糖基化稳定溶酶体膜。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-07-30 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402677

Yu-Shin Sou, Junji Yamaguchi, Keisuke Masuda, Yasuo Uchiyama, Yusuke Maeda, Masato Koike

{"title":"Golgi pH homeostasis stabilizes the lysosomal membrane through N-glycosylation of membrane proteins.","authors":"Yu-Shin Sou, Junji Yamaguchi, Keisuke Masuda, Yasuo Uchiyama, Yusuke Maeda, Masato Koike","doi":"10.26508/lsa.202402677","DOIUrl":"10.26508/lsa.202402677","url":null,"abstract":"Protein glycosylation plays a vital role in various cellular functions, many of which occur within the Golgi apparatus. The Golgi pH regulator (GPHR) is essential for the proper functioning of the Golgi apparatus. The lysosomal membrane contains highly glycosylated membrane proteins in abundance. This study investigated the role of the Golgi luminal pH in N-glycosylation of lysosomal membrane proteins and the effect of this protein modification on membrane stability using Gphr-deficient MEFs. We showed that Gphr deficiency causes an imbalance in the Golgi luminal pH, resulting in abnormal protein N-glycosylation, indicated by a reduction in sialylated glycans and markedly reduced molecular weight of glycoproteins. Further experiments using FRAP and PLA revealed that Gphr deficiency prevented the trafficking dynamics and proximity condition of glycosyltransferases in the Golgi apparatus. In addition, incomplete N-glycosylation of lysosomal membrane proteins affected lysosomal membrane stability, as demonstrated by the increased susceptibility to lysosomal damage. Thus, this study highlights the critical role of Golgi pH regulation in controlling protein glycosylation and the impact of Golgi dysfunction on lysosomal membrane stability.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855907","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

pyRBDome: a comprehensive computational platform for enhancing RNA-binding proteome data. pyRBDome：用于增强 RNA 结合蛋白质组数据的综合计算平台。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-07-30 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402787

Liang-Cui Chu, Niki Christopoulou, Hugh McCaughan, Sophie Winterbourne, Davide Cazzola, Shichao Wang, Ulad Litvin, Salomé Brunon, Patrick Jb Harker, Iain McNae, Sander Granneman

{"title":"pyRBDome: a comprehensive computational platform for enhancing RNA-binding proteome data.","authors":"Liang-Cui Chu, Niki Christopoulou, Hugh McCaughan, Sophie Winterbourne, Davide Cazzola, Shichao Wang, Ulad Litvin, Salomé Brunon, Patrick Jb Harker, Iain McNae, Sander Granneman","doi":"10.26508/lsa.202402787","DOIUrl":"10.26508/lsa.202402787","url":null,"abstract":"High-throughput proteomics approaches have revolutionised the identification of RNA-binding proteins (RBPome) and RNA-binding sequences (RBDome) across organisms. Yet, the extent of noise, including false positives, associated with these methodologies, is difficult to quantify as experimental approaches for validating the results are generally low throughput. To address this, we introduce pyRBDome, a pipeline for enhancing RNA-binding proteome data in silico. It aligns the experimental results with RNA-binding site (RBS) predictions from distinct machine-learning tools and integrates high-resolution structural data when available. Its statistical evaluation of RBDome data enables quick identification of likely genuine RNA-binders in experimental datasets. Furthermore, by leveraging the pyRBDome results, we have enhanced the sensitivity and specificity of RBS detection through training new ensemble machine-learning models. pyRBDome analysis of a human RBDome dataset, compared with known structural data, revealed that although UV-cross-linked amino acids were more likely to contain predicted RBSs, they infrequently bind RNA in high-resolution structures. This discrepancy underscores the limitations of structural data as benchmarks, positioning pyRBDome as a valuable alternative for increasing confidence in RBDome datasets.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855908","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

Kinesins regulate the heterogeneity in centrosome clustering after whole-genome duplication. 驱动蛋白调节全基因组复制后中心体集群的异质性

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-07-29 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402670

Thomas Ty Lau, Hoi Tang Ma, Randy Yc Poon

{"title":"Kinesins regulate the heterogeneity in centrosome clustering after whole-genome duplication.","authors":"Thomas Ty Lau, Hoi Tang Ma, Randy Yc Poon","doi":"10.26508/lsa.202402670","DOIUrl":"10.26508/lsa.202402670","url":null,"abstract":"After whole-genome duplication (WGD), tetraploid cells can undergo multipolar mitosis or pseudo-bipolar mitosis with clustered centrosomes. Kinesins play a crucial role in regulating spindle formation. However, the contribution of kinesin expression levels to the heterogeneity in centrosome clustering observed across different cell lines after WGD remains unclear. We identified two subsets of cell lines: \"BP\" cells efficiently cluster extra centrosomes for pseudo-bipolar mitosis, and \"MP\" cells primarily undergo multipolar mitosis after WGD. Diploid MP cells contained higher levels of KIF11 and KIF15 compared with BP cells and showed reduced sensitivity to centrosome clustering induced by KIF11 inhibitors. Moreover, partial inhibition of KIF11 or depletion of KIF15 converted MP cells from multipolar to bipolar mitosis after WGD. Multipolar spindle formation involved microtubules but was independent of kinetochore-microtubule attachment. Silencing KIFC1, but not KIFC3, promoted multipolar mitosis in BP cells, indicating the involvement of specific kinesin-14 family members in counteracting the forces from KIF11/KIF15 after WGD. These findings highlight the collective role of KIF11, KIF15, and KIFC1 in determining the polarity of the mitotic spindle after WGD.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792858","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

Gene expression and chromatin conformation of microglia in virally suppressed people with HIV. 病毒抑制型艾滋病患者小胶质细胞的基因表达和染色质构象。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-07-26 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402736

Johannes Cm Schlachetzki, Sara Gianella, Zhengyu Ouyang, Addison J Lana, Xiaoxu Yang, Sydney O'Brien, Jean F Challacombe, Peter J Gaskill, Kelly L Jordan-Sciutto, Antoine Chaillon, David Moore, Cristian L Achim, Ronald J Ellis, Davey M Smith, Christopher K Glass

{"title":"Gene expression and chromatin conformation of microglia in virally suppressed people with HIV.","authors":"Johannes Cm Schlachetzki, Sara Gianella, Zhengyu Ouyang, Addison J Lana, Xiaoxu Yang, Sydney O'Brien, Jean F Challacombe, Peter J Gaskill, Kelly L Jordan-Sciutto, Antoine Chaillon, David Moore, Cristian L Achim, Ronald J Ellis, Davey M Smith, Christopher K Glass","doi":"10.26508/lsa.202402736","DOIUrl":"10.26508/lsa.202402736","url":null,"abstract":"The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique \"Last Gift\" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766476","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

Late-life dietary folate restriction reduces biosynthesis without compromising healthspan in mice. 晚年叶酸膳食限制会减少小鼠的生物合成，但不会影响其健康寿命。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-07-23 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402868

Heidi M Blank, Staci E Hammer, Laurel Boatright, Courtney Roberts, Katarina E Heyden, Aravindh Nagarajan, Mitsuhiro Tsuchiya, Marcel Brun, Charles D Johnson, Patrick J Stover, Raquel Sitcheran, Brian K Kennedy, L Garry Adams, Matt Kaeberlein, Martha S Field, David W Threadgill, Helene L Andrews-Polymenis, Michael Polymenis

{"title":"Late-life dietary folate restriction reduces biosynthesis without compromising healthspan in mice.","authors":"Heidi M Blank, Staci E Hammer, Laurel Boatright, Courtney Roberts, Katarina E Heyden, Aravindh Nagarajan, Mitsuhiro Tsuchiya, Marcel Brun, Charles D Johnson, Patrick J Stover, Raquel Sitcheran, Brian K Kennedy, L Garry Adams, Matt Kaeberlein, Martha S Field, David W Threadgill, Helene L Andrews-Polymenis, Michael Polymenis","doi":"10.26508/lsa.202402868","DOIUrl":"10.26508/lsa.202402868","url":null,"abstract":"Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low-folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual's age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11266815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752056","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

Defective Integrator activity shapes the transcriptome of patients with multiple sclerosis. 多发性硬化症患者转录组的 "整合器 "活动缺陷。

IF 3.3 2区生物学

Life Science Alliance Pub Date : 2024-07-19 Print Date: 2024-10-01 DOI: 10.26508/lsa.202402586

Yevheniia Porozhan, Mikkel Carstensen, Sandrine Thouroude, Mickael Costallat, Christophe Rachez, Eric Batsché, Thor Petersen, Tove Christensen, Christian Muchardt

{"title":"Defective Integrator activity shapes the transcriptome of patients with multiple sclerosis.","authors":"Yevheniia Porozhan, Mikkel Carstensen, Sandrine Thouroude, Mickael Costallat, Christophe Rachez, Eric Batsché, Thor Petersen, Tove Christensen, Christian Muchardt","doi":"10.26508/lsa.202402586","DOIUrl":"10.26508/lsa.202402586","url":null,"abstract":"HP1α/CBX5 is an epigenetic regulator with a suspected role in multiple sclerosis (MS). Here, using high-depth RNA sequencing on monocytes, we identified a subset of MS patients with reduced CBX5 expression, correlating with progressive stages of the disease and extensive transcriptomic alterations. Examination of rare non-coding RNA species in these patients revealed impaired maturation/degradation of U snRNAs and enhancer RNAs, indicative of reduced activity of the Integrator, a complex with suspected links to increased MS risk. At protein-coding genes, compromised Integrator activity manifested in reduced pre-mRNA splicing efficiency and altered expression of genes regulated by RNA polymerase II pause-release. Inactivation of Cbx5 in the mouse mirrored most of these transcriptional defects and resulted in hypersensitivity to experimental autoimmune encephalomyelitis. Collectively, our observations suggested a major contribution of the Integrator complex in safeguarding against transcriptional anomalies characteristic of MS, with HP1α/CBX5 emerging as an unexpected regulator of this complex's activity. These findings bring novel insights into the transcriptional aspects of MS and provide potential new criteria for patient stratification.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727389","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