Life Science Alliance最新文献_第4页

Catalytic activity of KMT5B promotes ciliogenesis without affecting global chromatin accessibility. KMT5B的催化活性促进纤毛发生，而不影响整体染色质的可及性。

IF 3.1 2区生物学

Life Science Alliance Pub Date : 2026-04-07 Print Date: 2026-06-01 DOI: 10.26508/lsa.202503455

Janet Tait, Carmen Marthen, Barbara Hoelscher, Tobias Straub, Ohnmar Hsam, Ralph Aw Rupp

{"title":"Catalytic activity of KMT5B promotes ciliogenesis without affecting global chromatin accessibility.","authors":"Janet Tait, Carmen Marthen, Barbara Hoelscher, Tobias Straub, Ohnmar Hsam, Ralph Aw Rupp","doi":"10.26508/lsa.202503455","DOIUrl":"10.26508/lsa.202503455","url":null,"abstract":"Multiciliated cells (MCCs) are specialized cells found in the brain, reproductive and respiratory tracts of mammals, and the epidermis of tadpole-stage Xenopus embryos. KMT5B and KMT5C are histone methyltransferases that deposit the dimethyl mark on histone 4 lysine 20 (H4K20). We previously showed that KMT5B/C double knockdown down-regulates H4K20me2 levels in bulk chromatin, as well as transcription of ciliary genes. MCCs of embryos lacking both enzymes, or only KMT5B, have depleted cilia. Here, we separate the function of KMT5B in multiciliogenesis and show that single knockdown of KMT5B, not KMT5C, leads to aberrant transcription and down-regulation of ciliary genes. This phenotype is rescued by catalytically active PHF8, an H4K20me1 demethylase, whereas hormone-inducible multicilin (MCI), master regulator of cilia, has no effect. Notably, the expression of key transcription factors of ciliogenesis is unaffected by KMT5B depletion, which dominates the transcriptional response to ectopic multicilin. Finally, ATAC-seq in animal caps shows KMT5B knockdown results in few differentially accessible peaks and does not compact chromatin at ciliary genes. This suggests KMT5B regulates MCCs via an alternative pathway to the canonical MCI-driven programme.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13057974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633375","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

Optimization of systemic AAV9 gene therapy in Niemann-Pick disease, type C1 mice. AAV9基因治疗Niemann-Pick病C1型小鼠的优化研究

IF 3.1 2区生物学

Life Science Alliance Pub Date : 2026-03-30 Print Date: 2026-06-01 DOI: 10.26508/lsa.202402874

Avani V Mylvara, Alana L Gibson, Tansy Gu, Cristin D Davidson, Arturo A Incao, Katerina Melnyk, Susan R Gembic, Dominick Pierre-Jacques, Stephanie M Cologna, Charles P Venditti, Forbes D Porter, William J Pavan

{"title":"Optimization of systemic AAV9 gene therapy in Niemann-Pick disease, type C1 mice.","authors":"Avani V Mylvara, Alana L Gibson, Tansy Gu, Cristin D Davidson, Arturo A Incao, Katerina Melnyk, Susan R Gembic, Dominick Pierre-Jacques, Stephanie M Cologna, Charles P Venditti, Forbes D Porter, William J Pavan","doi":"10.26508/lsa.202402874","DOIUrl":"10.26508/lsa.202402874","url":null,"abstract":"Niemann-Pick disease, type C1 (NPC1), is a rare, fatal neurodegenerative disorder caused by pathological variants in NPC1, which encodes a lysosomal cholesterol transporter. FDA-approved treatments are limited and do not target the underlying genetic defect. Both systemic and central nervous system delivery of AAV9-hNPC1 have shown significant disease amelioration in NPC1 murine models. To assess the impact of dose in null Npc1 m1N/m1N mice, we systemically administered three different doses of AAV9-hNPC1 at 4 wk old. Then, to assess the impact of age, we administered the medium dose before phenotypic onset or at early or late stage of disease progression (4, 6, or 8 wk old, respectively). Higher vector doses and earlier treatment were associated with significantly increased lifespan, slower disease progression, and enhanced central nervous system transduction. In Npc1 I1061T/I1061T mice, a model recapitulating a common human hypomorphic variant, similar benefits ensued. Our findings help define dose ranges, treatment ages, and efficacy in hypomorphic models of NPC1 deficiency and suggest that higher doses of AAV9-hNPC1 in presymptomatic disease states are likely to yield better outcomes in NPC1 individuals.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13036363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581427","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

TaoChongBao: a large-scale C. elegans missense variant database bridging worm and human genomes. 陶崇宝：连接线虫与人类基因组的大型线虫错义变异数据库。

IF 3.1 2区生物学

Life Science Alliance Pub Date : 2026-03-23 Print Date: 2026-06-01 DOI: 10.26508/lsa.202603631

Ming Li, Shimin Wang, Yongping Chai, Zhengyang Guo, Zi Wang, Zhe Chen, Kexin Lei, Jingyi Ke, Xingshen Huang, Guanghan Chen, Peng Huang, Kaiming Xu, Zijie Shen, Wei Li, Guangshuo Ou

{"title":"TaoChongBao: a large-scale C. elegans missense variant database bridging worm and human genomes.","authors":"Ming Li, Shimin Wang, Yongping Chai, Zhengyang Guo, Zi Wang, Zhe Chen, Kexin Lei, Jingyi Ke, Xingshen Huang, Guanghan Chen, Peng Huang, Kaiming Xu, Zijie Shen, Wei Li, Guangshuo Ou","doi":"10.26508/lsa.202603631","DOIUrl":"10.26508/lsa.202603631","url":null,"abstract":"We generated and sequenced 12,069 viable Caenorhabditis elegans strains produced by ethyl methanesulfonate mutagenesis, identifying 20,315,536 variants, including 541,102 unique missense mutations across 20,914 genes. Most strains exhibit resistance to the anti-nematode drug ivermectin, whereas some others display phenotypes like dumpy morphology, uncoordinated movement, multivulva formation, and blistered cuticle. To organize and visualize this resource, we developed TaoChongBao, an open-access database and strain repository that integrates C. elegans mutation data with AlphaMissense-predicted pathogenicity scores and ClinVar clinical annotations. TaoChongBao enables users to explore worm missense variants, identify conserved residues corresponding to human pathogenic sites, and access viable strains for experimental validation. Compared with the previous Million Mutation Project in C. elegans, TaoChongBao expands mutation coverage over 20-fold and emphasizes amino acid-altering variants. This resource provides a scalable platform for functional residuomics, variant interpretation, and comparative analyses between C. elegans and human genomes.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13009681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513301","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

Huntingtin (HTT) interactome in regulation of DNA repair/remodeling and RNA processing pathways. 亨廷顿蛋白（HTT）在DNA修复/重塑和RNA加工途径调控中的相互作用。

IF 3.1 2区生物学

Life Science Alliance Pub Date : 2026-03-18 Print Date: 2026-06-01 DOI: 10.26508/lsa.202503424

Tamara Ratovitski, Chloe D Holland, Robert N O'Meally, Alexey V Shevelkin, Siddhi V Kamath, Tianze Shi, Matthew J Rodriguez, Robert N Cole, Mali Jiang, Christopher A Ross

{"title":"Huntingtin (HTT) interactome in regulation of DNA repair/remodeling and RNA processing pathways.","authors":"Tamara Ratovitski, Chloe D Holland, Robert N O'Meally, Alexey V Shevelkin, Siddhi V Kamath, Tianze Shi, Matthew J Rodriguez, Robert N Cole, Mali Jiang, Christopher A Ross","doi":"10.26508/lsa.202503424","DOIUrl":"10.26508/lsa.202503424","url":null,"abstract":"Huntington's disease (HD), an uncurable neurodegenerative disorder, is caused by CAG repeat expansion in the HD gene encoding mutant huntingtin protein. DNA damage response is implicated in HD pathogenesis. We used multiple approaches to assess normal and mutant HTT interactomes in the context of genotoxic stress. We show that double-strand break (DSB) repair response is impaired in HD neurons, which are more vulnerable to DSB-induced stress. We found that S1181 phosphorylation of HTT is regulated by DSB, and can be carried out by DNA-PK. Functional interaction of HTT with a major DSB kinase DNA-PKcs and association of both proteins with nuclear speckles suggest a role of HTT in DSB repair mechanism; however, physiological outcome of these interactions remains to be examined. We revealed HTT interactions with other proteins associated with nuclear speckles, TCERG1 and MED15, whose loci are genetic modifiers for HD, and with chromatin remodeling complex BAF. These interactions may position HTT as an important scaffolding intermediary providing integrated regulation of gene expression and RNA processing in the context of DNA repair mechanisms.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13000123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147480975","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

Histone methyltransferase DOT1L differentially affects the development of dendritic cell subsets. 组蛋白甲基转移酶DOT1L不同程度地影响树突状细胞亚群的发育。

IF 3.1 2区生物学

Life Science Alliance Pub Date : 2026-03-18 Print Date: 2026-06-01 DOI: 10.26508/lsa.202603624

Rianne G Bouma, Willem-Jan de Leeuw, Aru Z Wang, Muddassir Malik, Joeke Gc Stolwijk, Veronique Al Konijn, Anne Mensink, Natalie Proost, Maarten K Nijen Twilhaar, Tibor van Welsem, Negisa Seyed Toutounchi, Alsya J Affandi, Jip T van Dinter, Fred van Leeuwen, Joke Mm den Haan

{"title":"Histone methyltransferase DOT1L differentially affects the development of dendritic cell subsets.","authors":"Rianne G Bouma, Willem-Jan de Leeuw, Aru Z Wang, Muddassir Malik, Joeke Gc Stolwijk, Veronique Al Konijn, Anne Mensink, Natalie Proost, Maarten K Nijen Twilhaar, Tibor van Welsem, Negisa Seyed Toutounchi, Alsya J Affandi, Jip T van Dinter, Fred van Leeuwen, Joke Mm den Haan","doi":"10.26508/lsa.202603624","DOIUrl":"10.26508/lsa.202603624","url":null,"abstract":"Dendritic cells (DCs) orchestrate immune responses. Their development is controlled by transcription factors, but epigenetic mechanisms remain poorly understood. DOT1L emerges as a key epigenetic regulator in immune cells. Mapping DOT1L-mediated histone H3K79 methylation in canonical DC subsets revealed that DOT1L modified common and DC subset-specific genes. Deletion of Dot1l in vivo or in vitro decreased myeloid progenitors and increased cDC2s, whereas cDC1s remained unchanged. In addition, in vitro deletion of Dot1l led to loss of plasmacytoid DCs (pDCs) and of IFNα production upon stimulation. Upon in vivo deletion, a decrease in pDCs was only observed after subsequent in vitro expansion. This difference was likely related to insufficient replication-mediated loss of H3K79 methylation in vivo within the time frame studied. Transcriptomes of Dot1l-KO DC subsets exhibited enrichment of antigen presentation pathways, and MHC class II surface levels were up-regulated in pDCs. Mechanistically, inhibition of DOT1L linked the observed effects to its methyltransferase activity. Together, our data indicate that in DCs DOT1L differentially affects the development of canonical subsets and suppresses antigen presentation pathways.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13000122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147480991","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

Enzymes of physiological amyloidogenesis control pathological amyloid toxicity. 生理性淀粉样蛋白形成酶控制病理性淀粉样蛋白毒性。

IF 3.1 2区生物学

Life Science Alliance Pub Date : 2026-03-18 Print Date: 2026-06-01 DOI: 10.26508/lsa.202503493

Michael Bokros, Alex Grunfeld, Nathan C Balukoff, Jessica Bouviere, Eléonore Beurel, Stephen Lee

{"title":"Enzymes of physiological amyloidogenesis control pathological amyloid toxicity.","authors":"Michael Bokros, Alex Grunfeld, Nathan C Balukoff, Jessica Bouviere, Eléonore Beurel, Stephen Lee","doi":"10.26508/lsa.202503493","DOIUrl":"10.26508/lsa.202503493","url":null,"abstract":"Physiological amyloidogenesis drives the formation of functional amyloids involved in various biochemical pathways. We recently showed that the RNA tailing and decay machinery controls the maturation of intracellular amyloid-like aggregates. This raises the question of whether enzymes that participate in the maturation of physiological amyloids are involved in pathological amyloidogenesis implicated in human proteopathies. Using Caenorhabditis elegans and mouse models of pathological amyloids, we show that manipulating the RNA tailing-decay axis alters the toxicity of β-amyloid and α-synuclein involved in Alzheimer's and Parkinson's diseases, respectively. The RNA tailing enzymes TENT4b and TENT2 protect against β-amyloid- and α-synuclein-induced toxicity by facilitating the formation of nontoxic amyloidogenic assemblies. In contrast, the RNA exonuclease Exosc10 potentiates pathological amyloid toxicity. Remarkably, Exosc10 depletion prevents cognitive decline and restores memory in two different mouse models of β-amyloid neurotoxicity. Taken together, these results suggest that pathways of physiological amyloidogenesis participate in pathological amyloid etiology.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13000121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147481072","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

Dectin-1 epigenetic reprogramming rescues senescent-like Treg function in allergic asthma. Dectin-1表观遗传重编程可恢复过敏性哮喘中衰老样Treg功能。

IF 3.1 2区生物学

Life Science Alliance Pub Date : 2026-03-17 Print Date: 2026-06-01 DOI: 10.26508/lsa.202503552

Xiangdong Sun, Jiaqi Duan, Le Liu, Yanyu Ye, Yang Mi, Pengyuan Zheng, Pingchang Yang, Liguo Li

{"title":"Dectin-1 epigenetic reprogramming rescues senescent-like Treg function in allergic asthma.","authors":"Xiangdong Sun, Jiaqi Duan, Le Liu, Yanyu Ye, Yang Mi, Pengyuan Zheng, Pingchang Yang, Liguo Li","doi":"10.26508/lsa.202503552","DOIUrl":"10.26508/lsa.202503552","url":null,"abstract":"Allergic asthma is characterized by immune dysregulation, and deficiencies in regulatory T-cell (Treg) function are a hallmark of the disease. However, mechanisms of Treg impairment for their therapeutic correction remain poorly defined. The results showed that patient Tregs exhibited a senescent phenotype, including shortened telomeres, increased SA-β-gal activity, and heightened apoptosis. Functionally, they were compromised, showing reduced suppressive capacity and a pro-inflammatory cytokine shift. KQS-1 treatment robustly reversed these defects, restoring FOXP3- and IL-10-dependent Treg suppressive capacity and the production of anti-inflammatory cytokines. This functional rescue centered on these two core Treg signature genes was dependent on Dectin-1 binding and a downstream Raf-1/ROS signaling axis, which drove a sustained epigenetic program characterized by increased H3K4me3 and H3K27ac at the FOXP3 and IL10 loci, focal hypomethylation, and chromatin remodeling at these specific loci. CRISPR-mediated deletion of Dectin-1 abrogated all beneficial effects of KQS-1. As proof of principle that KQS1 is protective, we demonstrate attenuation of airway hyperresponsiveness, inflammation, and remodeling in dust mite-sensitized mice and in recipient mice upon adoptive transfer of KQS-1-trained human Tregs.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12996825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474275","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

TBXA2R activates ERMs to drive motility, invasion, and metastatic colonization of TNBC cells. TBXA2R激活erm，驱动TNBC细胞的运动性、侵袭性和转移性定植。

IF 3.1 2区生物学

Life Science Alliance Pub Date : 2026-03-17 Print Date: 2026-06-01 DOI: 10.26508/lsa.202503601

Kévin Leguay, Omaima Naffati, Camila Lie Kiyan, Yu Yan He, Mireille Hogue, Chloé Tesnière, Melania Gombos, Hellen Kuasne, Louis Gaboury, Christian Le Gouill, Sylvain Meloche, Michel Bouvier, Sébastien Carréno

{"title":"TBXA2R activates ERMs to drive motility, invasion, and metastatic colonization of TNBC cells.","authors":"Kévin Leguay, Omaima Naffati, Camila Lie Kiyan, Yu Yan He, Mireille Hogue, Chloé Tesnière, Melania Gombos, Hellen Kuasne, Louis Gaboury, Christian Le Gouill, Sylvain Meloche, Michel Bouvier, Sébastien Carréno","doi":"10.26508/lsa.202503601","DOIUrl":"10.26508/lsa.202503601","url":null,"abstract":"Cell migration and invasion are critical for cancer cell metastasis, relying on the ability of cells to adapt their morphology. Proteins of the ezrin, radixin, and moesin (ERM) family are key regulators of cell morphogenesis and essential determinants of cancer cell metastasis. However, the mechanisms by which ERMs are activated in metastatic cells remain poorly understood. We identified the thromboxane A2 receptor (TBXA2R), a G protein-coupled receptor overexpressed in multiple cancers, as a critical activator of ERMs, enhancing the motility and invasion of triple-negative breast cancer cells. We found that TBXA2R activates ERMs by engaging the Gαq/11 and Gα12/13 subfamilies, the Rho subfamily of Rho GTPases, and their Ser/Thr kinase effectors SLK and LOK. Furthermore, we demonstrate that TBXA2R promotes triple-negative breast cancer cell motility and invasion in vitro and metastatic colonization in vivo, dependent on ERM function. This reveals a novel signaling axis by which a member of the largest class of receptors activates key metastatic determinants, thereby controlling various aspects of metastasis. This discovery opens new avenues for developing targeted therapies against cancer metastasis.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12996826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474316","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

Mutual feedback regulation between Poly(A)-specific ribonuclease (PARN) and cognate microRNAs. 聚(A)特异性核糖核酸酶（PARN）与同源microrna之间的相互反馈调节。

IF 3.1 2区生物学

Life Science Alliance Pub Date : 2026-03-13 Print Date: 2026-05-01 DOI: 10.26508/lsa.202503341

Athanasios Kyritsis, Rafailia Aa Beta, Diana Scutelnic, Vasiliki Stravokefalou, Valerio Del Vescovo, Zoi V Arsenopoulou, Konstantinos Papikinos, Margherita Grasso, Francesca Fontana, Paraskevi Moutopoulou, Alexandros Tsiporis, Martina Samiotaki, George Panayotou, Michela A Denti, Nikolaos Aa Balatsos

{"title":"Mutual feedback regulation between Poly(A)-specific ribonuclease (PARN) and cognate microRNAs.","authors":"Athanasios Kyritsis, Rafailia Aa Beta, Diana Scutelnic, Vasiliki Stravokefalou, Valerio Del Vescovo, Zoi V Arsenopoulou, Konstantinos Papikinos, Margherita Grasso, Francesca Fontana, Paraskevi Moutopoulou, Alexandros Tsiporis, Martina Samiotaki, George Panayotou, Michela A Denti, Nikolaos Aa Balatsos","doi":"10.26508/lsa.202503341","DOIUrl":"10.26508/lsa.202503341","url":null,"abstract":"The majority of pri-miRNAs acquire a 5' cap and 3' poly(A) tail. Mature miRNAs recruit deadenylases that shorten poly(Α) tails triggering target mRNA degradation. Poly(A)-specific ribonuclease (PARN) is a deadenylase that also mediates late steps of noncoding RNA maturation. Herein, we show that PARN affects the expression of a subset of miRNAs in NCI-H520 cells of lung cancer origin, including miR-29a and miR-1207, which are also predicted to target PARN mRNA. PARN associates with pri-miR-29a and pri-miR-1207 regulating their poly(A) lengths. Conversely, miR-29a-3p and miR-1207-5p bind the 3' UTR of PARN mRNA and regulate its expression. Cleavage and polyadenylation specificity factor 6 (CPSF6) recruits PARN to pri-miRNAs and together they affect primary and mature miR-29a-3p levels. Modulation of PARN, miR-29a-3p, or miR-1207-5p expression affects cell migration. We present a model to describe the dynamic relation between PARN and miR-29a and discuss its biological significance.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12988311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147458291","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

RhoGEF Ect2 supports RhoA activity at cell-cell junctions through desmoplakin. RhoGEF Ect2通过桥蛋白支持RhoA在细胞-细胞连接处的活性。

IF 3.1 2区生物学

Life Science Alliance Pub Date : 2026-03-12 Print Date: 2026-06-01 DOI: 10.26508/lsa.202503454

Hoda Zarkoob, Chen Y Kam, Jennifer L Koetsier, Erin McCarthy, Avinash Jaiganesh, David P Kelsell, Farah Sheikh, Lisa M Godsel, Kathleen J Green

{"title":"RhoGEF Ect2 supports RhoA activity at cell-cell junctions through desmoplakin.","authors":"Hoda Zarkoob, Chen Y Kam, Jennifer L Koetsier, Erin McCarthy, Avinash Jaiganesh, David P Kelsell, Farah Sheikh, Lisa M Godsel, Kathleen J Green","doi":"10.26508/lsa.202503454","DOIUrl":"10.26508/lsa.202503454","url":null,"abstract":"Desmoplakin (DP) is an essential component of the desmosomal adhesion complex, tethering intermediate filaments to sites of intercellular adhesion to confer mechanical integrity to tissues. As a frequent target for mutation in cardiocutaneous syndromes that vary widely in phenotype, DP's roles as a signaling hub are rapidly emerging. Here, we identify the RhoGEF Ect2 as a previously unappreciated component of intercellular junctions in close association with DP. DP promotes the localization of Ect2 to keratinocyte desmosomes and cardiac intercalated discs, where it maintains active RhoA (Rho-GTP) at the membrane. We demonstrate that Ect2 activity is regulated by PKC in a DP-dependent manner in cardiac myocytes. Finally, a truncated form of DP expressed in patients with Carvajal syndrome associated with severe cardiocutaneous defects is impaired in its ability to bind and localize Ect2 to cell junctions in cardiomyocytes and patient keratinocytes. Our findings delineate an important relationship between a component of the desmosome and a critical regulator of actin cytoskeletal remodeling that could have widespread implications for understanding cardiac and cutaneous health and disease pathogenesis.","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 6","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12983042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444331","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