EMBO Journal最新文献_第4页

p53 regulates DREAM complex-mediated repression in a p21-independent manner.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-04 DOI: 10.1038/s44318-025-00402-7

Ritu Agrawal, Sagar Sengupta

{"title":"p53 regulates DREAM complex-mediated repression in a p21-independent manner.","authors":"Ritu Agrawal, Sagar Sengupta","doi":"10.1038/s44318-025-00402-7","DOIUrl":"https://doi.org/10.1038/s44318-025-00402-7","url":null,"abstract":"The DREAM repressor complex regulates genes involved in the cell cycle and DNA repair, vital for maintaining genome stability. Although it mediates p53-driven repression through the canonical p53-p21-Rb axis, the potential for p53 to directly regulate DREAM targets independently of its transcriptional activity has not been explored. Here, we demonstrate that in asynchronously growing cells, p53 loss leads to greater de-repression of DREAM targets compared to p21 loss alone. Both wild-type and transactivation-deficient p53 mutants are capable of repressing DREAM targets, suggesting a transactivation-independent \"non-canonical\" repression mechanism. These p53 variants bind p130/p107, irrespective of their phosphorylation status, while cancer-associated p53 mutants disrupt DREAM complex function by sequestering E2F4. Re-ChIP analysis shows co-recruitment of p53 and E2F4 to known and newly identified DREAM target promoters, indicating direct repression of these targets by p53. These findings reveal a novel, transactivation-independent mechanism of p53-mediated repression, expanding our understanding of p53's tumor-suppressive functions and suggesting DREAM complex targeting as potential future avenues in cancer therapy.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Noncanonical circRNA biogenesis driven by alpha and gamma herpesviruses.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-03 DOI: 10.1038/s44318-025-00398-0

Sarah E Dremel, Vishal N Koparde, Jesse H Arbuckle, Chad H Hogan, Thomas M Kristie, Laurie T Krug, Nicholas K Conrad, Joseph M Ziegelbauer

{"title":"Noncanonical circRNA biogenesis driven by alpha and gamma herpesviruses.","authors":"Sarah E Dremel, Vishal N Koparde, Jesse H Arbuckle, Chad H Hogan, Thomas M Kristie, Laurie T Krug, Nicholas K Conrad, Joseph M Ziegelbauer","doi":"10.1038/s44318-025-00398-0","DOIUrl":"https://doi.org/10.1038/s44318-025-00398-0","url":null,"abstract":"Herpesviruses require the host transcriptional machinery, inducing significant changes in gene expression to prioritize viral transcripts. We examined alpha- and gamma-herpesvirus alterations to a type of alternative splicing, namely circular RNA (circRNA) synthesis. We developed \"Circrnas in Host And viRuses anaLysis pIpEline\" (CHARLIE) to facilitate viral profiling. This method identified thousands of back-splicing variants, including circRNA common to lytic and latent phases of infection. Ours is the first report of Herpes Simplex Virus-1 circRNAs, including species derived from ICP0 and the latency-associated transcript. We characterized back-splicing cis- and trans-elements, and found viral circRNAs resistant to spliceosome perturbation and lacking canonical splice donor-acceptors. Subsequent loss-of-function studies of host RNA ligases (RTCB, RLIG1) revealed instances of decreased viral back splicing. Using eCLIP and 4sU-Sequencing, we determined that the KSHV RNA-binding protein, ORF57, enhanced synthesis for a subset of viral and host circRNAs. Our work explores unique splicing mechanisms driven by lytic infection, and identifies a class of transcripts with the potential to function in replication, persistence, or tumorigenesis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 Shu complex interacts with the replicative helicase to prevent mutations and aberrant recombination. Shu复合物与复制解旋酶相互作用以防止突变和异常重组。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-01-21 DOI: 10.1038/s44318-025-00365-9

Adeola A Fagunloye, Alessio De Magis, Jordan H Little, Isabela Contreras, Tanis J Dorwart, Braulio Bonilla, Kushol Gupta, Nathan Clark, Theresa Zacheja, Katrin Paeschke, Kara A Bernstein

{"title":"The Shu complex interacts with the replicative helicase to prevent mutations and aberrant recombination.","authors":"Adeola A Fagunloye, Alessio De Magis, Jordan H Little, Isabela Contreras, Tanis J Dorwart, Braulio Bonilla, Kushol Gupta, Nathan Clark, Theresa Zacheja, Katrin Paeschke, Kara A Bernstein","doi":"10.1038/s44318-025-00365-9","DOIUrl":"10.1038/s44318-025-00365-9","url":null,"abstract":"Homologous recombination (HR) is important for DNA damage tolerance during replication. The yeast Shu complex, a conserved homologous recombination factor, prevents replication-associated mutagenesis. Here we examine how yeast cells require the Shu complex for coping with MMS-induced lesions during DNA replication. We find that Csm2, a subunit of the Shu complex, binds to autonomous-replicating sequences (ARS) in yeast. Further evolutionary studies reveal that the yeast and human Shu complexes have co-evolved with specific replication-initiation factors. The connection between the Shu complex and replication is underlined by the finding that the Shu complex interacts with the ORC and MCM complexes. For example, the Shu complex interacts, independent of other HR proteins, with the replication initiation complexes through the N-terminus of Psy3. Lastly, we show interactions between the Shu complex and the replication initiation complexes are essential for resistance to DNA damage, to prevent mutations and aberrant recombination events. In our model, the Shu complex interacts with the replication machinery to enable error-free bypass of DNA damage.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1512-1539"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Mutations in the kinesin KIF12 promote MASH in humans and mice by disrupting lipogenic enzyme turnover.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-02-07 DOI: 10.1038/s44318-025-00366-8

Asieh Etemad, Yosuke Tanaka, Shuo Wang, Mordechai Slae, Mutaz Sultan, Orly Elpeleg, Nobutaka Hirokawa

{"title":"Mutations in the kinesin KIF12 promote MASH in humans and mice by disrupting lipogenic enzyme turnover.","authors":"Asieh Etemad, Yosuke Tanaka, Shuo Wang, Mordechai Slae, Mutaz Sultan, Orly Elpeleg, Nobutaka Hirokawa","doi":"10.1038/s44318-025-00366-8","DOIUrl":"10.1038/s44318-025-00366-8","url":null,"abstract":"As a common cause of liver cirrhosis, metabolic dysfunction-associated steatohepatitis (MASH) is regarded as a target of therapeutic intervention. However, a successful therapy has not yet been found, partly because the molecular pathogenesis is largely elusive. Here we show that KIF12 kinesin suppresses MASH development by accelerating the breakdown of two lipid biosynthesis enzymes, acetyl-CoA carboxylase 1 (ACC1) and pyruvate carboxylase (PC), in hepatocytes. We report three familial early-onset liver cirrhosis pedigrees with homozygous KIF12 mutations, accompanying MASH-like steatosis and cholestasis. The mouse genetic model carrying the corresponding Kif12 nonsense mutation faithfully reproduced the phenotypes as early as between 8 and 10 weeks of age. Furthermore, KIF12-deficient HepG2 cells exhibited significant steatosis, which was ameliorated by overexpressing a proline-rich domain (PRD) of KIF12. We found that KIF12-PRD promotes the degradation of ACC1 and PC, and this effect is likely to be through its direct interaction with these enzymes. Interestingly, KIF12 enhanced the ubiquitination of ACC1 by the E3 ligase COP1 and colocalized with these proteins as seen by super-resolution microscopy imaging. These data propose a role for KIF12 in suppressing MASH by accelerating turnover of lipogenic enzymes.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1608-1640"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Ephrin A1 functions as a ligand of EGFR to promote EMT and metastasis in gastric cancer. Ephrin A1作为EGFR配体促进胃癌EMT和转移。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-01-21 DOI: 10.1038/s44318-025-00363-x

Shuang Li, Meng Sun, Yun Cui, Dongyang Guo, Feng Yang, Qiang Sun, Yinuo Ding, Mengjie Li, Yiman Liu, Guangshuo Ou, Wei Zhuo, Tianhua Zhou

{"title":"Ephrin A1 functions as a ligand of EGFR to promote EMT and metastasis in gastric cancer.","authors":"Shuang Li, Meng Sun, Yun Cui, Dongyang Guo, Feng Yang, Qiang Sun, Yinuo Ding, Mengjie Li, Yiman Liu, Guangshuo Ou, Wei Zhuo, Tianhua Zhou","doi":"10.1038/s44318-025-00363-x","DOIUrl":"10.1038/s44318-025-00363-x","url":null,"abstract":"Distant metastasis is the major cause of gastric cancer mortality, and epidermal growth factor receptor (EGFR) activation plays critical roles in gastric cancer dissemination. However, EGFR targeting therapies in gastric cancer show only marginal effects, and the molecular mechanisms of oncogenic EGFR signaling remain poorly defined. Here, we report Ephrin A1 as a novel ligand of EGFR in gastric cancer. Ephrin A1 facilitates colonization and metastasis of gastric cancer cells in vitro and in vivo via inducing epithelial-mesenchymal transition (EMT). Ephrin A1 directly interacts with EGFR and induces EGFR dimerization, phosphorylation and activation of downstream signaling. Ephrin A1-induced EMT can be rescued by EGFR signaling inhibitors or knockout of EGFR, but not depletion of its classical receptor EphA2. Moreover, Ephrin A1 protein level correlates with EGFR phosphorylation levels in gastric cancer patients. Collectively, our work uncovers Ephrin A1 as a functional ligand of EGFR and highlights the potential role of the Ephrin A1/EGFR/EMT regulatory axis in cancer metastasis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1464-1487"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Multimodal mechanisms of human centriole engagement and disengagement. 人类中心粒参与和脱离的多模式机制

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-02-04 DOI: 10.1038/s44318-024-00350-8

Kei K Ito, Kasuga Takumi, Kyohei Matsuhashi, Hirokazu Sakamoto, Kaho Nagai, Masamitsu Fukuyama, Shohei Yamamoto, Takumi Chinen, Shoji Hata, Daiju Kitagawa

{"title":"Multimodal mechanisms of human centriole engagement and disengagement.","authors":"Kei K Ito, Kasuga Takumi, Kyohei Matsuhashi, Hirokazu Sakamoto, Kaho Nagai, Masamitsu Fukuyama, Shohei Yamamoto, Takumi Chinen, Shoji Hata, Daiju Kitagawa","doi":"10.1038/s44318-024-00350-8","DOIUrl":"10.1038/s44318-024-00350-8","url":null,"abstract":"Centrioles are unique cellular structures that replicate to produce identical copies, ensuring accurate chromosome segregation during mitosis. A new centriole, the \"daughter\", is assembled adjacent to an existing \"mother\" centriole. Only after the daughter centriole is fully developed as a complete replica, does it disengage and become the core of a new functional centrosome. The mechanisms preventing precocious disengagement of the immature daughter centriole have remained unclear. Here, we identify three key mechanisms maintaining mother-daughter centriole engagement: the cartwheel, the torus, and the pericentriolar material (PCM). Among these, the torus critically establishes the characteristic orthogonal engagement. We also demonstrate that engagement mediated by the cartwheel and torus is progressively released during centriole maturation. This release involves structural changes in the daughter, known as centriole blooming and distancing, respectively. Disrupting these structural transitions blocks subsequent steps, preventing centriole disengagement and centrosome conversion in the G1 phase. This study provides a comprehensive understanding of how the maturing daughter centriole progressively disengages from its mother through multiple steps, ensuring its complete structure and conversion into an independent centrosome.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1294-1321"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Stable centromere association of the yeast histone variant Cse4 requires its essential N-terminal domain. 酵母组蛋白变体Cse4的稳定着丝粒结合需要其必需的n端结构域。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-01-14 DOI: 10.1038/s44318-024-00345-5

Andrew R Popchock, Sabrine Hedouin, Yizi Mao, Charles L Asbury, Andrew B Stergachis, Sue Biggins

{"title":"Stable centromere association of the yeast histone variant Cse4 requires its essential N-terminal domain.","authors":"Andrew R Popchock, Sabrine Hedouin, Yizi Mao, Charles L Asbury, Andrew B Stergachis, Sue Biggins","doi":"10.1038/s44318-024-00345-5","DOIUrl":"10.1038/s44318-024-00345-5","url":null,"abstract":"Chromosome segregation relies on kinetochores that assemble on specialized centromeric chromatin containing a histone H3 variant. In budding yeast, a single centromeric nucleosome containing Cse4 assembles at a sequence-defined 125 bp centromere. Yeast centromeric sequences are poor templates for nucleosome formation in vitro, suggesting the existence of mechanisms that specifically stabilize Cse4 nucleosomes in vivo. The extended Cse4 N-terminal tail binds to the chaperone Scm3, and a short essential region called END within the N-terminal tail binds the inner kinetochore complex Okp1/Ame1. To address the roles of these interactions, we utilized single-molecule fluorescence assays to monitor Cse4 during kinetochore assembly. We found that Okp1/Ame1 and Scm3 independently stabilize Cse4 at centromeres via their END interaction. Scm3 and Cse4 stability at the centromere are enhanced by Ipl1/Aurora B phosphorylation of the Cse4 END, identifying a previously unknown role for Ipl1 in ensuring Cse4 stability. Strikingly, a phosphomimetic mutation in the Cse4 END restores Cse4 recruitment in mutants defective in Okp1/Ame1 binding. Together, these data suggest that a key function of the essential Cse4 N-terminus is to ensure Cse4 localization at centromeres.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1488-1511"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Coordination between ESCRT function and Rab conversion during endosome maturation.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-02-05 DOI: 10.1038/s44318-025-00367-7

Daniel P Ott, Samit Desai, Jachen A Solinger, Andres Kaech, Anne Spang

{"title":"Coordination between ESCRT function and Rab conversion during endosome maturation.","authors":"Daniel P Ott, Samit Desai, Jachen A Solinger, Andres Kaech, Anne Spang","doi":"10.1038/s44318-025-00367-7","DOIUrl":"10.1038/s44318-025-00367-7","url":null,"abstract":"The endosomal pathway is essential for regulating cell signaling and cellular homeostasis. Rab5 positive early endosomes receive proteins from the plasma membrane. Dependent on a ubiquitin mark on the protein, they will be either recycled or sorted into intraluminal vesicles (ILVs) by endosomal sorting complex required for transport (ESCRT) proteins. During endosome maturation Rab5 is replaced by Rab7 on endosomes that are able to fuse with lysosomes to form endolysosomes. However, whether ESCRT-driven ILV formation and Rab5-to-Rab7 conversion are coordinated remains unknown. Here we show that loss of early ESCRTs led to enlarged Rab5 positive endosomes and prohibited Rab conversion. Reduction of ubiquitinated cargo alleviated this phenotype. Moreover, ubiquitinated proteins on the endosomal limiting membrane prevented the displacement of the Rab5 guanine nucleotide exchange factor (GEF) RABX-5 by the GEF for Rab7, SAND-1/CCZ-1. Overexpression of Rab7 could partially overcome this block, even in the absence of SAND-1 or CCZ1, suggesting the presence of a second Rab7 GEF. Our data reveal a hierarchy of events in which cargo corralling by ESCRTs is upstream of Rab conversion, suggesting that ESCRT-0 and ubiquitinated cargo could act as timers that determine the onset of Rab conversion.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1574-1607"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Mitochondrial DNA removal is essential for sperm development and activity.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-02-11 DOI: 10.1038/s44318-025-00377-5

Zhe Chen, Fan Zhang, Annie Lee, Michaela Yamine, Zong-Heng Wang, Guofeng Zhang, Christian Combs, Hong Xu

{"title":"Mitochondrial DNA removal is essential for sperm development and activity.","authors":"Zhe Chen, Fan Zhang, Annie Lee, Michaela Yamine, Zong-Heng Wang, Guofeng Zhang, Christian Combs, Hong Xu","doi":"10.1038/s44318-025-00377-5","DOIUrl":"10.1038/s44318-025-00377-5","url":null,"abstract":"Active mitochondrial DNA (mtDNA) elimination during spermatogenesis has emerged as a conserved mechanism ensuring the uniparental mitochondrial inheritance in animals. However, given the existence of post-fertilization processes degrading sperm mitochondria, the physiological significance of mtDNA removal during spermatogenesis is not clear. Here we show that mtDNA clearance is indispensable for sperm development and activity. We uncover a previously unappreciated role of Poldip2 as a mitochondrial exonuclease that is specifically expressed in late spermatogenesis and required for sperm mtDNA elimination in Drosophila. Loss of Poldip2 impairs mtDNA clearance in elongated spermatids and impedes the progression of individualization complexes that strip away cytoplasmic materials and organelles. Over time, poldip2 mutant sperm exhibit marked nuclear genome fragmentation, and the flies become completely sterile. Notably, these phenotypes were rescued by expressing a mitochondrially targeted bacterial exonuclease, which ectopically removes mtDNA. Our work illustrates the developmental necessity of mtDNA clearance for effective cytoplasm removal at the end of spermatid morphogenesis, and for preventing potential nuclear-mitochondrial genome imbalance in mature sperm, in which nuclear genome activity is shut down.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1749-1773"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Somatostatin triggers local cAMP and Ca²⁺ signaling in primary cilia to modulate pancreatic β-cell function.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-02-12 DOI: 10.1038/s44318-025-00383-7

Ceren Incedal Nilsson, Özge Dumral, Gonzalo Sanchez, Beichen Xie, Andreas Müller, Michele Solimena, Huixia Ren, Olof Idevall-Hagren

{"title":"Somatostatin triggers local cAMP and Ca2+ signaling in primary cilia to modulate pancreatic β-cell function.","authors":"Ceren Incedal Nilsson, Özge Dumral, Gonzalo Sanchez, Beichen Xie, Andreas Müller, Michele Solimena, Huixia Ren, Olof Idevall-Hagren","doi":"10.1038/s44318-025-00383-7","DOIUrl":"10.1038/s44318-025-00383-7","url":null,"abstract":"Somatostatin, released from δ-cells within pancreatic islets of Langerhans, is one of the most important negative regulators of islet hormone secretion. We find that islet δ-cells are positioned near, and release somatostatin onto, primary cilia of the other islet cell types, including insulin-secreting β-cells. Somatostatin activates ciliary somatostatin receptors, resulting in rapid lowering of the ciliary cAMP concentration which in turn promotes more sustained nuclear translocation of the cilia-dependent transcription factor GLI2 through a mechanism that operates in parallel with the canonical Hedgehog pathway and depends on ciliary Ca2+ signaling. We also find that primary cilia length is reduced in islets from human donors with type-2 diabetes, which is associated with a reduction in interactions between δ-cells and cilia. Our findings show that islet cell primary cilia constitute an important target of somatostatin action, which endows somatostatin with the ability to regulate islet cell function beyond acute suppression of hormone release.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1663-1691"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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