PLoS Genetics最新文献

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Age-associated decline of Coenzyme A leads to intestinal stem cells dysfunction via disturbing iron homeostasis. 年龄相关的辅酶A下降通过扰乱铁稳态导致肠道干细胞功能障碍。
IF 4 2区 生物学
PLoS Genetics Pub Date : 2025-05-30 DOI: 10.1371/journal.pgen.1011704
Zhiming Liu, Gang Du, Yi Chen, Haiyang Chen
{"title":"Age-associated decline of Coenzyme A leads to intestinal stem cells dysfunction via disturbing iron homeostasis.","authors":"Zhiming Liu, Gang Du, Yi Chen, Haiyang Chen","doi":"10.1371/journal.pgen.1011704","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011704","url":null,"abstract":"<p><p>The decline in adult stem cell performance is closely linked to tissue malfunction and the rising incidence of age-related diseases. To investigate the molecular basis of these impairments, our screening strategy identified reduced activity in the pantothenate/coenzyme A (CoA) pathway within aged ISCs. Furthermore, exogenous CoA supplementation restructured ISC metabolic pathways, reversing age-induced hyperproliferation and intestinal dysfunction, and thus extending Drosophila lifespan by curbing excessive iron accumulation in ISCs. These findings uncover a new mechanism of stem cell aging and propose that pantothenate and CoA could be potential therapeutic targets for treating age-related diseases and enhancing healthy aging in humans.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011704"},"PeriodicalIF":4.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188356","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
The Slx4-Rad1-Rad10 nuclease differentially regulates deletions and duplications induced by a replication fork barrier. Slx4-Rad1-Rad10核酸酶差异调控由复制叉屏障诱导的缺失和复制。
IF 4 2区 生物学
PLoS Genetics Pub Date : 2025-05-30 DOI: 10.1371/journal.pgen.1011720
Marina K Triplett, Iffat Ahmed, Swathi Shekharan, Lorraine S Symington
{"title":"The Slx4-Rad1-Rad10 nuclease differentially regulates deletions and duplications induced by a replication fork barrier.","authors":"Marina K Triplett, Iffat Ahmed, Swathi Shekharan, Lorraine S Symington","doi":"10.1371/journal.pgen.1011720","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011720","url":null,"abstract":"<p><p>Genomic instability is a hallmark of cancer that can be caused by DNA replication stress. Copy number variation (CNV) is a type of genomic instability that has been associated with both tumorigenesis and drug resistance, but how these structural variants form in response to replication stress is not fully understood. Here, we established a direct repeat genetic reporter in Saccharomyces cerevisiae to detect recombination events that result in either a duplication or a deletion. Using this system, we measured recombination resulting from site-specific replication fork stalling initiated by Tus binding to an array of Ter sites. We found that a Tus/Ter fork block downstream of direct repeats induced CNV by a mechanism involving the Mph1 translocase, Exo1-catalyzed end resection and Rad51-dependent strand invasion. While the Slx4 scaffold protein and its nuclease-binding partner, Rad1, were shown to be required for duplications, we found that they suppress deletion formation in this context. These opposing functions suggest that both recombination products arise through a large loop heteroduplex intermediate that is cleaved by Rad1-Rad10 in a manner that promotes duplications and eliminates deletions. Taken together, these studies give insight into the mechanisms governing CNV in the context of replication fork stalling, which may ultimately provide a better understanding of how replication stress contributes to cancer and other diseases characterized by genome instability.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011720"},"PeriodicalIF":4.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188338","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
Cross-tissue coordination between SLC nucleoside transporters regulates reproduction in Caenorhabditis elegans. SLC核苷转运体之间的跨组织协调调节秀丽隐杆线虫的繁殖。
IF 4 2区 生物学
PLoS Genetics Pub Date : 2025-05-30 DOI: 10.1371/journal.pgen.1011425
Youchen Guan, Yong Yu, Shihong M Gao, Lang Ding, Qian Zhao, Meng C Wang
{"title":"Cross-tissue coordination between SLC nucleoside transporters regulates reproduction in Caenorhabditis elegans.","authors":"Youchen Guan, Yong Yu, Shihong M Gao, Lang Ding, Qian Zhao, Meng C Wang","doi":"10.1371/journal.pgen.1011425","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011425","url":null,"abstract":"<p><p>Metabolism is fundamental to organism physiology and pathology. From the intricate network of metabolic reactions, diverse chemical molecules, collectively termed metabolites, are produced. In multicellular organisms, metabolite communication between different tissues is vital for maintaining homeostasis and adaptation. However, the molecular mechanisms mediating these metabolite communications remain poorly understood. Here, we focus on nucleosides and nucleotides, essential metabolites involved in multiple cellular processes, and report the pivotal role of the SLC29A family of transporters in mediating nucleoside coordination between the soma and the germline. Through genetic analysis, we discovered that two Caenorhabditis elegans homologs of SLC29A transporters, Equilibrative Nucleoside Transporter ENT-1 and ENT-2, act in the germline and the intestine, respectively, to regulate reproduction. Their knockdown synergistically results in sterility. Further single-cell transcriptomic and targeted metabolomic profiling revealed that the ENT double knockdown specifically affects genes in the purine biosynthesis pathway and reduces the ratio of guanosine to adenosine levels. Importantly, guanosine supplementation into the body cavity/pseudocoelom through microinjection rescued the sterility caused by the ENT double knockdown, whereas adenosine microinjection had no effect. Together, these studies support guanosine as a rate-limiting factor in the control of reproduction, uncover the previously unknown nucleoside/nucleotide communication between the soma and the germline essential for reproductive success, and highlight the significance of SLC-mediated cell-nonautonomous metabolite coordination in regulating organism physiology.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011425"},"PeriodicalIF":4.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188337","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
An integrative approach to prioritize candidate causal genes for complex traits in cattle. 牛复杂性状候选因果基因优先排序的综合方法。
IF 4 2区 生物学
PLoS Genetics Pub Date : 2025-05-30 DOI: 10.1371/journal.pgen.1011492
Mohammad Ghoreishifar, Iona M Macleod, Amanda J Chamberlain, Zhiqian Liu, Thomas J Lopdell, Mathew D Littlejohn, Ruidong Xiang, Jennie E Pryce, Michael E Goddard
{"title":"An integrative approach to prioritize candidate causal genes for complex traits in cattle.","authors":"Mohammad Ghoreishifar, Iona M Macleod, Amanda J Chamberlain, Zhiqian Liu, Thomas J Lopdell, Mathew D Littlejohn, Ruidong Xiang, Jennie E Pryce, Michael E Goddard","doi":"10.1371/journal.pgen.1011492","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011492","url":null,"abstract":"<p><p>Genome-wide association studies (GWAS) have identified many quantitative trait loci (QTL) associated with complex traits, predominantly in non-coding regions, posing challenges in pinpointing the causal variants and their target genes. Three types of evidence can help identify the gene through which QTL acts: (1) proximity to the most significant GWAS variant, (2) correlation of gene expression with the trait, and (3) the gene's physiological role in the trait. However, there is still uncertainty about the success of these methods in identifying the correct genes. Here, we test the ability of these methods in a comparatively simple series of traits associated with the concentration of polar lipids in milk. We conducted single-trait GWAS for ~14 million imputed variants and 56 individual milk polar lipid (PL) phenotypes in 336 cows. A multi-trait meta-analysis of GWAS identified 10,063 significant SNPs at FDR ≤ 10% (P ≤ 7.15E-5). Transcriptome data from blood (~12.5K genes, 143 cows) and mammary tissue (~12.2K genes, 169 cows) were analyzed using the genetic score omics regression (GSOR) method. This method links observed gene expression to genetically predicted phenotypes and was used to find associations between gene expression and 56 PL phenotypes. GSOR identified 2,186 genes in blood and 1,404 in mammary tissue associated with at least one PL phenotype (FDR ≤ 1%). We partitioned the genome into non-overlapping windows of 100 Kb to test for overlap between GSOR-identified genes and GWAS signals. We found a significant overlap between these two datasets, indicating that GSOR-significant genes were more likely to be located within 100 Kb windows that include GWAS signals than those that do not (P = 0.01; odds ratio = 1.47). These windows included 70 significant genes expressed in mammary tissue and 95 in blood. Compared to all expressed genes in each tissue, these genes were enriched for lipid metabolism gene ontology (GO). That is, seven of the 70 significant mammary transcriptome genes (P < 0.01; odds ratio = 3.98) and five of the 95 significant blood genes (P < 0.10; odds ratio = 2.24) were involved in lipid metabolism GO. The candidate causal genes include DGAT1, ACSM5, SERINC5, ABHD3, CYP2U1, PIGL, ARV1, SMPD5, and NPC2, with some overlap between the two tissues. The overlap between GWAS, GSOR, and GO analyses suggests that together, these methods are more likely to identify genes mediating QTL, though their power remains limited, as reflected by modest odds ratios. Larger sample sizes would enhance the power of these analyses, but issues like linkage disequilibrium would remain.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011492"},"PeriodicalIF":4.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188336","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
Variant-specific priors clarify colocalisation analysis. 变异特异性先验澄清了共定位分析。
IF 4 2区 生物学
PLoS Genetics Pub Date : 2025-05-27 DOI: 10.1371/journal.pgen.1011697
Jeffrey M Pullin, Chris Wallace
{"title":"Variant-specific priors clarify colocalisation analysis.","authors":"Jeffrey M Pullin, Chris Wallace","doi":"10.1371/journal.pgen.1011697","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011697","url":null,"abstract":"<p><p>Linking GWAS variants to their causal gene and context remains an ongoing challenge. A widely used method for performing this analysis is the coloc package for statistical colocalisation analysis, which can be used to link GWAS and eQTL associations. Currently, coloc assumes that all variants in a region are equally likely to be causal, despite the success of fine-mapping methods that use additional information to adjust their prior probabilities. In this paper we propose and implement an approach for specifying variant-specific prior probabilities in the coloc method. We describe and compare six source of information for specifying prior probabilities: non-coding constraint, enhancer-gene link scores, the output of the PolyFun method and three estimates of eQTL-TSS distance densities. Using simulations and analysis of ground-truth pQTL-eQTL colocalisations we show that variant-specific priors, particularly the eQTL-TSS distance density priors, can improve colocalisation performance. Furthermore, across GWAS-eQTL colocalisations variant-specific priors changed colocalisation significance in up to 14.1% of colocalisations, at some loci revealing the likely causal gene.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011697"},"PeriodicalIF":4.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163132","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
The ubiquitin ligase HUWE1 enhances WNT signaling by antagonizing destruction complex-mediated β-catenin degradation and through a mechanism independent of changes in β-catenin abundance. 泛素连接酶HUWE1通过拮抗破坏复合体介导的β-连环蛋白降解,并通过独立于β-连环蛋白丰度变化的机制增强WNT信号。
IF 4 2区 生物学
PLoS Genetics Pub Date : 2025-05-27 DOI: 10.1371/journal.pgen.1011677
Joseph K McKenna, Yalan Wu, Praveen Sonkusre, Caleb K Sinclear, Raj Chari, Andres M Lebensohn
{"title":"The ubiquitin ligase HUWE1 enhances WNT signaling by antagonizing destruction complex-mediated β-catenin degradation and through a mechanism independent of changes in β-catenin abundance.","authors":"Joseph K McKenna, Yalan Wu, Praveen Sonkusre, Caleb K Sinclear, Raj Chari, Andres M Lebensohn","doi":"10.1371/journal.pgen.1011677","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011677","url":null,"abstract":"<p><p>WNT/β-catenin signaling is mediated by the transcriptional coactivator β-catenin (CTNNB1). CTNNB1 abundance is regulated by phosphorylation and proteasomal degradation, promoted by a destruction complex composed of the scaffold proteins APC and AXIN1 or AXIN2, and the kinases casein kinase 1α (CSNK1A1) and GSK3A or GSK3B. Loss of CSNK1A1 increases CTNNB1 abundance, resulting in hyperactive WNT signaling. Previously, we demonstrated that the HECT domain E3 ubiquitin ligase HUWE1 is necessary for hyperactive WNT signaling in HAP1 haploid human cells lacking CSNK1A1. Here, we investigated the mechanism underlying this requirement. In HAP1 cells lacking CSNK1A1, GSK3A/GSK3B still phosphorylated a fraction of CTNNB1, promoting its degradation. HUWE1 loss enhanced GSK3A/GSK3B-dependent CTNNB1 phosphorylation, further reducing CTNNB1 abundance. However, the reduction in CTNNB1 caused by HUWE1 loss was smaller than the reduction in WNT target gene transcription. To test whether the reduction in WNT signaling caused by HUWE1 loss resulted from reduced CTNNB1 alone, we engineered the endogenous CTNNB1 locus in HAP1 cells to encode a CTNNB1 variant insensitive to destruction complex-mediated phosphorylation and degradation. HUWE1 loss in these cells did not change CTNNB1 abundance but still reduced WNT signaling, demonstrating that another mechanism was at play. Genetic interaction and overexpression analyses revealed that the reduction in WNT signaling caused by HUWE1 loss required not only GSK3A or GSK3B, but also APC and AXIN1. Therefore, in HAP1 cells lacking CSNK1A1, a residual destruction complex containing APC, AXIN1 and GSK3A or GSK3B downregulates WNT signaling by phosphorylating and targeting CTNNB1 for degradation, and HUWE1 enhances WNT signaling by antagonizing this activity. Regulation of WNT signaling by HUWE1 also requires its ubiquitin ligase activity. We conclude that HUWE1 enhances WNT/CTNNB1 signaling through two mechanisms, one that antagonizes destruction complex-mediated CTNNB1 degradation and another that is independent of changes in CTNNB1 abundance. Coordinated regulation of CTNNB1 abundance and a second signaling step by HUWE1 would be an efficient way to control WNT signaling output, enabling sensitive and robust activation of the pathway.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011677"},"PeriodicalIF":4.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163091","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
Contribution of the tobamovirus resistance gene Tm-1 to control of tomato brown rugose fruit virus (ToBRFV) resistance in tomato. 烟草病毒抗性基因Tm-1对控制番茄褐皱果病毒抗性的贡献
IF 4 2区 生物学
PLoS Genetics Pub Date : 2025-05-23 DOI: 10.1371/journal.pgen.1011725
Avner Zinger, Adi Doron-Faigenboim, Dana Gelbart, Ilan Levin, Moshe Lapidot
{"title":"Contribution of the tobamovirus resistance gene Tm-1 to control of tomato brown rugose fruit virus (ToBRFV) resistance in tomato.","authors":"Avner Zinger, Adi Doron-Faigenboim, Dana Gelbart, Ilan Levin, Moshe Lapidot","doi":"10.1371/journal.pgen.1011725","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011725","url":null,"abstract":"<p><p>Tomato brown rugose fruit virus (ToBRFV) is a rapidly spreading pathogen that poses a significant threat to tomato production worldwide. We previously identified a locus on tomato chromosome 11 controlling tolerance to the virus. We further established that combining this locus with one that maps to the Tm-1 region on chromosome 2 confers resistance to the virus. Here we sought to determine whether, and how, the Tm-1 gene itself is involved in ToBRFV resistance. Overexpression of Tm-1 in a tolerant genotype significantly reduced viral accumulation, conferring resistance to ToBRFV. On the other hand, overexpression of Tm-1 in a susceptible genotype only delayed symptom appearance. Moreover, effective RNAi-silencing of Tm-1 in the resistant genotype yielded susceptible plants. These findings show that the Tm-1 gene interacts genetically with the locus controlling tolerance on chromosome 11 and that this interaction is critical for achieving effective resistance to ToBRFV. In addition, the symptomatic plants obtained following silencing of Tm-1 in the resistant genotype indicate that tolerance is also dependent on normal expression levels of the recessive tm-1 allele.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011725"},"PeriodicalIF":4.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133353","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
New composite phenotypes enhance chronic kidney disease classification and genetic associations. 新的复合表型增强慢性肾脏疾病的分类和遗传关联。
IF 4 2区 生物学
PLoS Genetics Pub Date : 2025-05-23 DOI: 10.1371/journal.pgen.1011718
Kim Ngan Tran, Heidi G Sutherland, Andrew J Mallett, Lyn R Griffiths, Rodney A Lea
{"title":"New composite phenotypes enhance chronic kidney disease classification and genetic associations.","authors":"Kim Ngan Tran, Heidi G Sutherland, Andrew J Mallett, Lyn R Griffiths, Rodney A Lea","doi":"10.1371/journal.pgen.1011718","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011718","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is a multifactorial condition driven by diverse etiologies that lead to a gradual loss of kidney function. Although genome-wide association studies (GWAS) have identified numerous genetic loci linked to CKD, a large portion of its genetic basis remains unexplained. This knowledge gap may partly arise from the reliance on single biomarkers, such as estimated glomerular filtration rate (eGFR), to assess kidney function. To address this limitation, we developed and applied a novel multi-phenotype approach, combinatorial Principal Component Analysis (cPCA), to better understand the complex genetic architecture of CKD. Using UK Biobank dataset (n = 337,112), we analyzed 21 CKD-related phenotypes, generating over 2 million composite phenotypes (CPs) through cPCA. Nearly 50,000 of these CPs demonstrated significantly higher classification power for clinical CKD compared to individual biomarkers. The top-ranked CP-a combination of albumin, cystatin C, eGFR, gamma-glutamyltransferase, HbA1c, low-density lipoprotein, and microalbuminuria, achieved an AUC of 0.878 (95% CI: 0.873-0.882), significantly outperforming eGFR alone (AUC: 0.830, 95% CI: 0.825-0.835). Genetic association analysis of the ~ 50,000 high-performing CPs identified all major eGFR-associated loci, except for the SH2B3 locus rs3184504, a loss-of-function variant, which was uniquely identified in CPs (p = 3.1[Formula: see text]10-56) but not in eGFR within the same sample size. In addition, SH2B3 locus showed strong evidence of colocalization with eGFR, supporting its role in kidney function. These results highlight the power of the multi-phenotype cPCA approach in understanding the genetic basis of CKD, with potential applications to other complex diseases.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011718"},"PeriodicalIF":4.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133359","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
Maximal inhibitory effect of MOV10 on LINE-1 retrotransposition requires both the MOV10/LINE-1 association and granule formation. MOV10对LINE-1逆转录的最大抑制作用需要MOV10/LINE-1结合和颗粒形成。
IF 4 2区 生物学
PLoS Genetics Pub Date : 2025-05-23 DOI: 10.1371/journal.pgen.1011709
Qian Liu, Yaqi Liu, Yang Mao, Dongrong Yi, Quanjie Li, Jiwei Ding, Saisai Guo, Yongxin Zhang, Jing Wang, Jianyuan Zhao, Ling Ma, Xiaozhong Peng, Shan Cen, Xiaoyu Li
{"title":"Maximal inhibitory effect of MOV10 on LINE-1 retrotransposition requires both the MOV10/LINE-1 association and granule formation.","authors":"Qian Liu, Yaqi Liu, Yang Mao, Dongrong Yi, Quanjie Li, Jiwei Ding, Saisai Guo, Yongxin Zhang, Jing Wang, Jianyuan Zhao, Ling Ma, Xiaozhong Peng, Shan Cen, Xiaoyu Li","doi":"10.1371/journal.pgen.1011709","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011709","url":null,"abstract":"<p><p>LINE-1 is the only active autonomous mobile element in the human, and its mobilization is tightly restricted by the host to maintain genetic stability. We recently reported that human MOV10 recruits DCP2 to decap LINE-1 RNA by liquid-liquid phase separation (LLPS), resulting in the inhibition of LINE-1 retrotransposition, while the detailed mechanism still awaits further exploration. In this report, we found that the extended motif II (563-675aa) and the C-terminal domain (907-1003aa) of MOV10 cooperated to achieve maximal inhibition on LINE-1 retrotransposition. The extended motif II involves the interaction between MOV10 and LINE-1, and the C-terminal domain is required for MOV10's association with G3BP1 and thereby the formation of granules. The association with LINE-1 through the extended motif II is dominantly attributed to MOV10-mediated anti-LINE-1 activity. On this basis, promoting large granules formation by the C-terminal domain warrants maximal inhibition of LINE-1 replication by MOV10. These data together shed light on the detailed mechanism underlying MOV10-mediated inhibition of LINE-1 retrotransposition, and provide further evidence supporting the important role of MOV10-driven granules in the anti-LINE-1 action.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011709"},"PeriodicalIF":4.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133358","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 SanA as a novel regulator of peptidoglycan biogenesis in Escherichia coli. SanA在大肠杆菌中作为肽聚糖生物生成新调控因子的鉴定。
IF 4 2区 生物学
PLoS Genetics Pub Date : 2025-05-22 DOI: 10.1371/journal.pgen.1011712
Bhargavi Gundavarapu, Krishna Chaitanya Nallamotu, Vishnu Vachana Murapaka, Balaji Venkataraman, Lutikurti Saisree, Manjula Reddy
{"title":"Identification of SanA as a novel regulator of peptidoglycan biogenesis in Escherichia coli.","authors":"Bhargavi Gundavarapu, Krishna Chaitanya Nallamotu, Vishnu Vachana Murapaka, Balaji Venkataraman, Lutikurti Saisree, Manjula Reddy","doi":"10.1371/journal.pgen.1011712","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011712","url":null,"abstract":"<p><p>Gram-negative bacterial cell envelope consists of a surface-exposed lipid bilayer (outer membrane or OM) that serves as a permeability barrier to maintain the cellular integrity. Beneath the OM is the periplasmic space that harbours peptidoglycan (PG), a highly cross-linked mesh-like glycan polymer closely encasing the inner membrane (IM). During growth of a bacterium balanced synthesis of the envelope components is required to maintain the cellular integrity, of which little is known. In this study, we identify sanA, an ORF of unknown function encoding a predicted IM-anchored protein as a factor contributing to balanced synthesis of PG in E. coli. Absence of SanA increased the rate of nascent PG strand incorporation, and restored growth and viability to several mutants defective in either cell division or cell elongation. Detailed mutant analysis of sanA showed that it is defective in the envelope barrier properties. Interestingly, overexpression of the periplasmic endopeptidases that cleave the cross-links of the PG mesh was able to alleviate the phenotypes of sanA mutant implying the envelope defects are due to alterations in the PG sacculus. Additionally, a SanA variant (SSDsbA-SanA) targeted to the periplasm, complemented the SanA- phenotypes suggesting it functions in the periplasmic phase of the PG synthesis. Further, we find that SanA functions independently of its paralog, ElyC, known to regulate the synthesis of enterobacterial common antigen (ECA), a surface polysaccharide found in the cell envelopes of most enteric bacteria. Overall, our results suggest a role for SanA in the maintenance of optimal PG synthesis, providing evidence for the existence of an additional layer of regulation in Gram-negative cell envelope biogenesis.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011712"},"PeriodicalIF":4.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128980","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
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